Novel approaches to the development of tyrosine kinase inhibitors and their role in the fight against cancer.

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Review

Novel approaches to the development of tyrosine kinase inhibitors and their role in the fight against cancer

1.

Introduction

2.

Role of TKIs in cancer

3.

Conclusion

Adriana Za´mecˇnı´kova

4.

Expert opinion

Kuwait Cancer Control Center, Department of Hematology, Laboratory of Cancer Genetics, Kuwait

Introduction: Protein tyrosine kinase inhibitors are currently one of the most important classes of cancer drugs and one of the most impressive approaches of targeted cancer therapy. Aberrant activation of tyrosine kinase pathways is among the most dysregulated molecular pathways in human cancers; therefore, a large number of tyrosine kinases may serve as valuable molecular targets. To date, several inhibitors of tyrosine kinases have been approved and there are hundreds more compounds that are in various stages of development. Because of the deregulation in human malignancies, the ABL1, SRC, the epidermal growth factor receptor and the vascular endothelial growth factor receptor kinases are among the protein kinases that are considered as prime molecular targets for selective inhibition. Areas covered: This review focuses on most important small-molecule inhibitors that serve as a model for future development. They also provide a broad overview of some of the new approaches and challenges in the field. Expert opinion: With the exception of a few malignancies seemingly driven by a limited number of genetic lesions, current targeted therapeutic approaches have shown only limited efficacy in advanced cancers. Consequently, more sophisticated strategies, such as identification of pathogenic ‘driver’ mutations and optimization of personalized therapies are needed. Keywords: BCR-ABL1 inhibitors, epidermal growth factor receptor, targeted therapy, tyrosine kinase inhibitors, vascular endothelial growth factor receptor Expert Opin. Drug Discov. [Early Online]

1.

Introduction

Tyrosine kinases (TKs) are essential enzymes that constitute one of the largest and most functionally diverse families of protein kinases. To date, > 90 protein TKs have been found in the human genome comprising two main families: the transmembrane receptor-linked kinases and the non-RTKs families. Humans have 58 known receptor TKs (RTKs) and 32 cytoplasmic non-receptor types, which can be further clustered into groups, families and subfamilies [1]. Function of TKs RTKs are cell surface receptors essential for transduction of extracellular signals into the cell, while non-RTKs lack a transmembrane segment and functions in intracellular communications. RTKs and non-RTKs catalyze the transfer of a phosphoryl group from a nucleoside triphosphate donor to the hydroxyl group of tyrosine residues on protein substrates. Phosphorylation of tyrosine residues causes a change in the function of the protein-creating binding sites for the recruitment of downstream signaling proteins. This, in turn, triggers a cascade of events through phosphorylation of several signaling proteins that ultimately affect gene transcription 1.1

10.1517/17460441.2014.865012 © 2013 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X All rights reserved: reproduction in whole or in part not permitted

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Z. Adriana

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Oncogene-specific activation of TK networks has emerged as one of the most frequent mechanism of oncogenesis in human cancer. Accordingly, TKs which are key oncogenic drivers in various tumors are valuable targets for selective inhibition. The success of TKIs in the treatment of CML is a powerful vindication of the concept of gene-targeted therapy and demonstrates that a small-molecule inhibitor has the potential to alter the natural course of the disease. TKI monotherapy may be particularly effective in malignancies driven by identifiable mutations of one or a few genes, critical for disease pathogenesis. Presently available TKIs have not thus far shown diseasemodifying activity in advanced solid tumors and many of them extend patients’ lives beyond existing treatment modalities for only months or not at all. The high complexity of solid tumors, which develop as a consequence of multiple genetic alterations, has provided rationales for selecting inhibitors of multiple kinases and novel combination therapies attacking different targets. The shift to combinatorial approaches has introduced new challenges, such as identification of an appropriate target and effective combination of drug cocktails, while minimizing patient exposure to unnecessary toxicities and significant cost of therapy. Cancer is today recognized as a dynamically complex disease, specific to the individual neoplasm. This underscores the challenge of applying ‘one-size-fits-all’ therapeutic approaches for all patients. Future strategies are likely to rely on the ability to recognize genomic features of individual tumors and identification of patient populations that are likely to respond.

This box summarizes key points contained in the article.

within the nucleus [2,3]. Phosphorylation of signal transduction molecules is one of the key modifications that occur in multicellular organisms and plays a central role in diverse biological processes. Because TKs are key regulators of cell function, their catalytic activity is tightly controlled allowing a cell to respond appropriately to its environment. Therefore, strict regulation of kinase activity controls the most fundamental processes of cells such as cellular proliferation, differentiation, apoptosis as well as various regulatory processes [3].

increased kinase activity and increased translation [3,4]. Given that oncogenic TKs are pleiotropic, multiple pathways have effects on cellular proteins, all of which could contribute to initiation or progression of cancer. 2.

Role of TKIs in cancer

Given the critical role of TKs in malignant transformation, their inhibition seems to be an attractive approach for therapeutic interventions. To this effect, numerous agents have been, and continue to be, discovered that are in various stages of development. Among these, the most extensive clinical and laboratory characterization has been performed for the Abelson murine leukemia viral oncogene homolog 1 (ABL1), SRC family kinases (SFKs), epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) family members. Cellular TKIs Non-RTKs play a central role in signal transduction and regulate a broad variety of physiological cell processes. Several non-RTKs can be found in human cells, which can be further subdivided in 11 families based on their structural similarities and biochemical functions. Non-RTKIs are regularly found to be mutated or overexpressed in human malignancies, including leukemias, myeloproliferative disorders and solid tumors [1,4]. Because of their deregulation in various malignancies, many inhibitors were developed to target members of non-RTK families (Table 1). Among them, the ABL1 and SRC family members were the first kinases to be considered for targeted therapies. Owing to the structural homology between SRC and ABL1, several TKIs originally developed as SRC inhibitors have later be found to have ABL1 inhibitor activity [5,6]. In addition, the first inhibitor of the Janusassociated kinases (JAKs) family Jakafi (ruxolitinib, Incyte Corp.) was approved for the treatment of patients with myelofibrosis. Several other compounds (TG101348 SAR302503, CEP701 or LY2784544) are being tested for the treatment of myeloproliferative neoplasms and some of the immunemediated disorders [7-9]. 2.1

BCR-ABL1 inhibitors The chimeric BCR-ABL1 gene, the product of the Philadelphia (Ph) chromosome translocation t(9;22)(q34;q11.1), is the etiological agent of chronic myeloid leukemia (CML) and less frequently of acute lymphoblastic leukemia (ALL). BCR-ABL1 is the founding member of a family of oncogenic TKs, which include TEL-ABL1, TEL-JAK2, TEL-PDGFR and JAK2V617F, deregulated in chronic myeloproliferative disorders [10,11]. The enhanced kinase activity of BCR-ABL1 is attributed to be the major driver of disease transformation, considered to be necessary and sufficient for leukemogenesis [12]. Therefore, inhibition of its activity is a particularly 2.1.1

1.2

Activation of TKs in cancer

Aberrant catalytic activity of many TKs results in dysregulation of signal transduction pathways and plays an important role in numerous pathological conditions, including cancer. There is convincing evidence that excessive phosphorylation that arise during the course of malignancy is a major activating event in cancer. Therefore, many TKs are regularly found to be mutated or expressed at high levels in cancer. Dysregulation of TK signaling may arise by different mechanisms, including mutation, chromosome translocation, gene amplification or overexpression of ‘upstream’ molecules that lead to 2

Expert Opin. Drug Discov. (2013) 9(1)

Novel approaches to the development of TKIs and their role in the fight against cancer

Table 1. Selected small-molecule inhibitors of cellular TKs.


Inhibitor

TK target

Comments

BCR-ABL1/SRC inhibitors Bosutinib (Bosulif)

BCR/ABL1/SRC

Dasatinib (Sprycel)

BCR/ABL1/SRC, PDGFR-b, KIT, EPHA2

Imatinib (Gleevec)

BCR-ABL1, KIT, ARG, FMS, PDGFR-b, LYN

Nilotinib (Tasigna)

BCR-ABL1, PDGFR-b, KIT, CSF-1R DDR1

Omexatidine (Synribo)

Protein translation inhibitor

Ponatinib (Iclusig)

BCR-ABL1, PDGFRa, FLT3, KIT, VEGFR2, RET

Rebastinib (DCC-2036)

ABL switch pocket inhibitor

Saracatinib (AZD0530)

SRC/ABL1

JAK inhibitors Lestaurtinib (CEP-701) Pacritinib (SB1518)

JAK2, FLT3, TRKA, TRKB, TRKC JAK2

Ruxolitinib (Jakafi)

JAK1/JAK2

Approved as a second-line therapy for CML (2012) Approved as a second-line therapy for CML and Ph+ ALL (2006) and as a first-line therapy for CML (2010) Approved as a first-line therapy for CML (2001), KIT+ GIST (2002), PDGFR rearranged MDS/MPD, ASM (D816V-negative c-KIT) and HES/CEL with FIP1L1-PDGFR (2006) Approved as a second-line therapy for CML (2007) and as a first-line therapy for CML (2010) Approved as a third-line treatment for CML (2012). Targets BCR-ABL1 mutations, including T315I Approved in 2012 as a second-line therapy for CML and Ph+ ALL. Targets BCR-ABL1 mutations, including T315I Phase I/II clinical trials in CML patients. Targets T315I ABL1 Phase I/II studies in solid tumors Phase II clinical trials for AML and MPD Phase II/III clinical trials for lymphoma and myeloid malignancies Approved for intermediate and high risk myelofibrosis (2011)

ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; ASM: Aggressive systemic mastocytosis; CML: Chronic myeloid leukemia; GIST: Gastrointestinal stromal tumors; HES/CEL: Hypereosinophilic syndrome/chronic eosinophilic leukemia; MDS/MPD: Myelodysplastic/myeloproliferative diseases; Ph+: Philadelphiapositive chromosome.

attractive strategy for disease modification. From the discovery of the pathogenic role of the BCR-ABL1, several compounds have been discovered, facilitated by structural studies [13]. Imatinib, the first powerful TKI in cancer therapy The first powerful ABL1 kinase inhibitor to gain clinical approval was imatinib mesylate (marketed as Gleevec or Glivec; previously known as STI-571, Novartis Pharma Stein AG). Imatinib is a synthetic drug which has been identified by high-throughput screen of chemical libraries. It targets the adenosine triphosphate (ATP)-binding site of different TKs, including BCR-ABL1, PDGFR, Abelson-related gene (ARG) and c-KIT. Its competitive binding at the ATPbinding site of BCR-ABL1 results in subsequent disruption of oncogenic signaling leading to apoptotic death of Ph+ cells [13-15]. 2.1.1.1

TKIs have emerged as a standard therapy for CML The introduction of imatinib into routine clinical practice in 2001 resulted in unprecedented responses, with complete cytogenetic responses in up to 80% of patients treated in early chronic phase. Importantly, a substantial fraction of patients 2.1.1.2

achieve a complete molecular response with undetectable levels of BCR-ABL1, a response rarely seen in cancer therapy [16,17]. These outstanding clinical responses rapidly led to clinical trials in other malignancies associated with activation of TKs. Imatinib had already demonstrated efficiency and has been approved in other cancers such as c-KIT (CD117)+ gastrointestinal stromal tumor (GIST), metastatic dermatofibrosarcoma protuberans and aggressive systemic mastocytosis (ASM) without the D816V c-KIT mutation. In addition, it is approved for the treatment of patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with PDGFR gene rearrangements and advanced hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL) with FIP1L1-PDGFR rearrangement [11,18]. Mechanism of resistance Despite the success story of imatinib, some patients are refractory or develop resistance to the drug. BCR-ABL1 point mutations that generally occur in the ATP-binding pocket are the most commonly reported cause of resistance and are detected in ~ 60% of patients [19,20]. However, a number of other mechanisms of resistance exist, such as BCR-ABL1 2.1.1.3


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gene amplification and BCR-ABL1-independent mechanisms such as disruptions in drug uptake and efflux and activation of alternative signaling pathways. Recently, an overexpression of SFKs has been reported as a mechanism of BCR-ABL1independent imatinib resistance and it has been showed that dual SFKs and BCR-ABL1 inhibition induces an enhanced apoptotic response [19-21]. To overcome imatinib resistance, more potent TKIs were developed. The first TKI, dasatinib (Sprycel, formerly BMS-354825, Bristol-Myers Squibb), a broad-spectrum kinase inhibitor, was originally developed as an SRC inhibitor and was later found to be a powerful agent in most CML patients [22,23]. Nilotinib (trade name Tasigna, formerly AMN107) was introduced by Novartis just a year after the launch of imatinib. This new molecule was created to be more specific and more potent than imatinib, making it effective against most imatinib-resistant kinase mutations. Nilotinib binds 20 -- 50 times more tightly than imatinib to BCR-ABL1 and inhibits c-KIT and PDGFR, but not SRC. These second-generation TKIs were rapidly developed, thus demonstrating how understanding of resistance mechanisms may facilitate the development of new and more effective drugs. Both, nilotinib and dasatinib were originally approved to treat patients who failed previous imatinib therapy, but both were approved in 2010 for the treatment of newly diagnosed CML patients. Importantly, results of clinical trials demonstrated their superiority in meeting early response end points and lower rates of progression compared with imatinib [24-26]. These more powerful inhibitors have activity against most kinase domain mutations that confer resistance to imatinib, with the prominent exception of the T315I mutation that confers resistance to imatinib, dasatinib and nilotinib [25-27].

Recent therapies in CML To address resistant T315I mutation problem, additional kinase inhibitors have been developed. Among them, two drugs have just been approved for second- or third-line therapy: bosutinib (Bosulif, formerly SKI-606, Pfizer, Inc.) and ponatinib (Iclusig or AP24534, Ariad Pharmaceuticals, Inc.). The dual SRC/ABL1 inhibitor bosutinib can overcome most imatinib-resistant BCR-ABL1-1 mutations, again except the T315I and V299L mutant cells [28,29]. At present, the only TKI to be able to overcome the uniformly resistant T315I mutation is a pan-BCR-ABL1 inhibitor ponatinib. Ponatinib was designed using Ariad’s computational-based drug design platform. In heavily pretreated patients with relapsed or refractory chronic-phase CML, ponatinib produced hematological response in 100% and a major cytogenetic response in 92% of patients, including 70% of patients who had a T315I mutation. In addition, it selectively inhibits certain other TKs implicated in the pathogenesis of acute myeloid leukemia (AML) and other hematological malignancies such as FMS-like TK 3 (FLT3), 2.1.1.4

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RET, KIT, members of the fibroblast growth factor receptor 1 (FGFR1) and the PDGFR families of kinases [30]. Omacetaxine mepesuccinate (Ceflatonin, Synribo, Chemgenex Therapeutics, Inc.) has been approved for the treatment of adult CML patients who have failed two or more TKIs. Omacetaxine is a reversible protein translation inhibitor that provides clinical activity regardless of BCRAB1L mutation status [31]. Similarly, the ABL1 ‘switch-control’ inhibitor, DCC-2036, has shown efficacy in patients carrying highly imatinib-resistant BCR-ABL1 kinase isoforms, including T315I. Other TKIs are under development and these include bafetinib (INNO-406), agents with opportunistic cross-activity against T315I, such as Aurora kinase inhibitors (MK-0457, XL228, PHA-739358 and KW-2449), arsenic trioxide and histone deacetylase (HDAC) inhibitors. More experimental agents, which are under investigation alone or in combination include VX-680, BIRB-796, ONO 12380, the dual JAK2/ABL1 kinase inhibitor ON044580, HSP90 inhibitors, mammalian target of rapamycin (mTOR) inhibitors and other substances [32,33]. SRC family of TKs The SRC family of kinases is the largest family of non-RTKs that have been extensively studied over the past few decades. SFKs can interact with various RTKs, such as EGFR and VEGFR, which are involved in activation of several pathways regulating proliferation, angiogenesis, cell motility, invasion and bone metabolism. Members of the SRC family are dysregulated in multiple malignances and their transforming ability is linked to the ability of activating key signaling molecules, rather than through direct activity [5,34]. Blocking SRC activation has been a goal of cancer therapy for many years and, indeed, the SFKs are one of the best-characterized targets for cancer therapy. Of particular interest is Schmidt-Ruppin A-2 (c-SRC), the cellular counterpart of the first identified viral oncogene v-Src, high levels of which are found in various cancers including breast, colon, lung cancers and bone metastases. Numerous agents that target c-SRC are currently in clinical trials, including dasatinib, bosutinib, saracatinib (AZD0530), KX01 and KX2-391 [5,6]. Perhaps the most promising is dasatinib, a dual SRC/ ABL1 inhibitor, which has been approved for the treatment of Ph+ leukemias. The key enzyme in the development of these diseases is BCR-ABL1, where SRC is also involved. Dasatinib also inhibits other TKs, such as c-KIT, PDGFRa/b and ephrin receptors. Dasatinib has inhibitory effect on cell duplication, migration and tumoral microenvironment and it triggers apoptosis of cancer cells [35]. Dasatinib is currently in clinical trials for different cancers, including non-Hodgkin’s lymphoma, metastatic breast cancer and prostate cancer. It is also currently being tested in non-small-cell lung cancer (NSCLC) with gefitinib-resistant EGFR mutations and in combination with erlotinib [36]. It is also under development in association with chemotherapy or other targeted therapies in melanoma (dasatinib plus dacarbazine), 2.1.2



prostate cancer (dasatinib plus docetaxel) and colorectal cancer (dasatinib plus oxaliplatin plus capecitabine). Many Phase I/II trials studying dasatinib in combination with other agents are under way in breast, head and neck, glioblastoma and colorectal cancers [5,35,37]. However, despite being the oldest known proto-oncogene and despite decades of research, currently developed SRC inhibitors have shown only minimal therapeutic activity in solid tumors. While dual SRC/ABL1 inhibitors (dasatinib and bosutinib) have proven efficiency in CML, they have shown little clinical activity in solid tumors [37,38]. Overview of RTKs RTKs are cell surface receptors composed of an extracellular ligand-binding domain, a transmembrane domain, an intracellular catalytic domain with TK activity and additional amino acid sequences that function as regulatory domains. Ligand binding induces receptor dimerization of two RTKs leading to autophosphorylation of tyrosine residues and initiation of downstream signaling cascades [3,4]. Many RTKs are involved in oncogenesis, either by overexpression, amplification and/or activating mutations. In every case, the result is a dysregulated RTK signaling and excessive phosphorylation that sustains signal transduction pathways in an activated state. A number of RTK inhibitors (RTKIs) has already been approved or has shown promise in clinical trials for the treatment of various malignancies. Among them, the most intensive studies were performed with inhibitors targeting the EGFR and the VEGFR family members [1-4].


2.2

EGFR family of receptors and therapeutic agents EGFRs are transmembrane TK receptors that belong to the human epidermal growth factor receptor (HER) family of receptors comprising four related proteins: EGFR, HER2, HER3 and HER4 (also called HER1/ERBB1, ERBB2, ERBB3 and ERBB4) [1,2,39]. EGFRs are activated by binding to several ligands, including epidermal growth factor (EGF), transforming growth factor-a and heparin-binding EGF-like growth factor. Ligand binding to the extracellular binding domain induces receptor dimerization between members of the HER family either as result of heterodimerization or homodimerization, which in turn activates other critical pathways driving proliferation, cell survival, angiogenesis and migration. High levels of EGFRs play an important role in solid tumors of epithelial origin and are associated with aggressive forms of several human cancers, including lung carcinomas, breast, colorectal, prostate, renal, ovarian and primary brain cancers [40,41]. Given the prominent role of EGFR signaling in human cancer, EGFRs have been extensively researched since the early 1980s. At present, there are two main approaches to target EGFR: monoclonal antibodies directed against the extracellular domain of EGFR and inactivation of EGFR signaling using RTKIs (Table 2). These include anti-EGFR antibodies (trastuzumab, cetuximab and panitumumab) and 2.2.1

small-molecule inhibitors, such as erlotinib, gefitinib and lapatinib [39,42]. Targeting EGFR: experience with first-generation inhibitors

2.2.1.1

Gefitinib (Iressa, AstraZeneca Pharmaceuticals LP) was the first approved EGFR inhibitor for patients with advanced NSCLC [43]. EGFR-dependent pathways play an important role in the development and progression of NSCLC where EGFR overexpression appears to promote solid tumor growth [44]. The activity of gefitinib was originally tested in unselected patients with advanced NSCLC and initial results were encouraging showing rapid symptom improvement and tumor regressions. However, results from large-scale prospective studies (INTACT 1, INTACT 2 and ISEL) demonstrated no improvement in overall survival in patients receiving gefitinib versus chemotherapy. Analyses of these and following Phase III trials showed that the presence of EGFR mutation was the strongest predictor of improved progression-free survival [44,45]. The majority of these patients had mutations in the EGFR kinase domain affecting, most often, exon 19 deletions or exon 21 (L858R) substitution mutations. Consequently, EGFR mutation has been widely studied as a potential predictive factor for TKI efficacy [46,47]. Erlotinib (Tarceva, Genentech/OSI Pharmaceuticals, Inc.), is a selective EGFR inhibitor which was first approved in 2004 as a monotherapy for the treatment of metastatic NSCLC and in combination with gemcitabine for advanced pancreatic cancer patients in 2005. Based on the results of multicenter randomized trials in NSCLC patients harboring EGFR exon 19 deletions or exon 21 mutations, erlotinib is currently being used as a first-line therapy for EGFR mutation positive NSCLC [48,49]. It is usually preferred to gefitinib; but both compounds are under investigation in combination with chemotherapy in several solid tumors [1,2,39]. EGFR TKI resistance The use of small-molecule TKIs that selectively target the intracellular TK domain of EGFR resulted in improved progression-free rates of patients with advanced tumors, particularly those harboring activating EGFR mutations. Nevertheless, despite initial responses, acquired resistance eventually emerged in these patients [50,51]. Two major mechanisms of resistance were identified: secondary mutations (T790M and less frequently D761Y, L747S and T854A) and amplification of the mesenchymal-epithelial transition factor (MET) oncogene. MET amplification has been observed in up to 20% of tumor samples after TKI therapy and up to one-third of patient harbor concurrent T790M mutation and MET amplification. Several additional mechanisms of resistance have been identified, including altered insulin-like growth factor receptor signaling, phosphatidylinositol 3¢-kinase (PI3K)CA mutation, loss of phosphatase and tensin homolog expression, as well as EGFR nuclear transport, all of which may contribute to treatment 2.2.1.2


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Table 2. Selected TKIs of the EGFR TK family. Inhibitor

Class


Target

Afatinib (Gilotrif )

Small molecule

EGFR/ERBB2

Canertinib (CI-1033)

Irreversible inhibitor

EGFR/ERBB2/3/4

Cetuximab (Erbitux)

Monoclonal antibody

EGFR

Dacomitinib (PF-0299804) Erlotinib (Tarceva)

Irreversible inhibitor Small molecule

pan-HER EGFR

Gefitinib (Iressa)

Small molecule

EGFR

Icotinib (BPI-2009H)

Small molecule

EGFR

Lapatinib (Tykerb)

Small molecule

HER2 ERB1/2

Neratinib (HKI-272)

Irreversible inhibitor

ERBB2 EGFR

Panitumumab (Vectibix) Pertuzumab (Perjeta)

Monoclonal antibody Monoclonal antibody

EGFR EGFR HER2

Trastuzumab (Herceptin)

Monoclonal antibody

HER2

Description Approved as a first-line treatment for NSCLC with EGFR exon 19 deletions/exon 21 mutations (2013) Phase II studies in metastatic NSCLC and breast cancer Approved for metastatic CRC (2004) and NSCLC (2006); first-line therapy for EGFRexpressing KRAS mutation-negative CRC (2012) Phase II/III for advanced NSCLC Approved for advanced NSCLC (2004); pancreatic cancer (2005); NSCLC with mutated EGFR (2013) Approved for advanced NSCLC (2003; modified in 2005) and inhibits mutated EGFR Phase IV trial in EGFR-mutated NSCLC; metastatic brain tumor Approved for HER2-overexpressing breast cancer (2007) Phase I/II breast cancer and other solid tumors Approved for metastatic colon cancer (2006) Approved for HER2-overexpressing breast cancer (2012) Approved for HER2-overexpressing breast cancer (2006) and metastatic gastric or gastroesophageal junction adenocarcinoma (2010)

CRC: Colorectal carcinoma; NSCLC: Non-small-cell lung cancer.

failure [50-52]. To overcome such resistance, novel irreversible or multi-targeted TKIs have been developed. Most of these next-generation TKIs target more than one receptor in addition to EGFR, such as HER2 and VEGFR2, and therefore have the potential to improve patient outcomes in EGFR/ HER2-driven solid tumors [42,45,51,52]. Lapatinib (lapatinib ditosylate, Tyverb/Tykerb, GlaxoSmithKline), which simultaneously inhibits EGFR and HER2, is used in conjunction with capecitabine (Xeloda) in patients with advanced metastatic HER2+ breast cancer. Because EGFR and HER2 are expressed in up to 30% of esophageal squamous cell carcinomas, its potential utility either alone or in combination (cetuximab/herceptin, 5-fluorouracil) is under investigation. Other clinical studies with metastatic breast cancer, NSCLC and colorectal cancers are in progress [53,54]. Irreversible EGFR inhibitors Irreversible EGFR inhibitors, which covalently bind to cysteine residues in the kinase domain, are novel therapeutic approaches in cancer therapy. This characteristic may result in prolonged inhibition of ATP binding and potentially greater clinical effects. Recently, a number of clinical trials have been initiated to explore the use of irreversible EGFR inhibitors, which include afatinib, neratinib and canertinib. 2.2.1.3

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Afatinib (Gilotrif, afatinib dimaleate, Boehringer Ingelheim International GmbH) is a newly approved drug for the first-line treatment of patients with metastatic NSCLC harboring common EGFR mutations. Afatinib is an irreversibly multikinase inhibitor of EGFR, HER2, HER4 and VEGFR2. In contrast to first-generation TKIs, it can also bind to EGFR carrying the T790M mutation. Its approval was based on the demonstration of high response rates and promising progression-free survivals in patients with EGFR mutationpositive advanced NSCLC. Because of its additional activity against HER2, it is also investigated for clinical use in HER2+ breast cancer and other EGFR/HER2-driven cancers such as prostate, head and neck cancers and glioma [55-57]. In contrast to gefitinib and erlotinib, canertinib (CI-1033) irreversibly inhibits all EGFR family members that have been shown to have activity against a variety of cancers. Recently, it was shown that it has antiproliferative and apoptotic effects on AML cells expressing mutated FLT3, leading to significant apoptosis induction, thus suggesting that canertinib can be a novel treatment option for AML [58,59]. Similar to afatinib and canertinib, neratinib (HKI-272) is an irreversible TKI with both HER2 and EGFR TKI activity. Neratinib is under investigation in clinical trials both as a monotherapy and in combinations in HER2+ metastatic breast cancer and advanced NSCLC [60].



Pertuzumab Trastuzumab

Anti-ligand monoclonal antibodies (1)

Ligands

Cetuximab Panitumumab EGFR

HER2

(5) Hormonal therapy (Tamoxifen)

(6) Radiotherapy Tyrosine kinase inhibitors


(2)

Erlotinib Gefitinib

P

P

P

P

(4) Signal transducer inhibitors RAF

(3) Multitargeted inhibitors

PI3K

Apatinib Lapatinib Neratinib

RAS MEK

MAPK Proliferation

mTOR

Gene transcription Cell cycle progression

Metastasis

AKT

BAD Cell survival/ apoptosis Differentiation

(7) Chemotherapy

Figure 1. EGFR and HER2 family pathways in cancer and current drugs that target these proteins in cancer are shown. The activity of EGFR family members can be inhibited either by using humanized monoclonal antibodies (1) or single target (2) or multi-targeted (3) small-molecule TKIs. TKIs could be used in combination or in sequence with inhibitors of downstream signal transduction pathways (4). In addition, they can be used with other therapies such as hormonal therapy (5), radiation therapies (6) and may also be combined with chemotherapies (7). Inspired by [4,34]. EGFR: Epidermal growth factor receptor; HER2: Human epidermal growth factor receptor 2.

Combination therapies Several trials have been performed to assess the efficacy of first-line EGFR inhibitors in combined approaches (Figure 1). These include the use of gefitinib or erlotinib in combination with mTOR inhibitors (everolimus), PI3K inhibitors (BKM120), Akt inhibitor (MK2206), proteasome inhibitor (bortezomib), HDAC inhibitors (entinostat, vorinostat) and others. Further studies are being performed to assess the combined effect of ERGR inhibitors with other targeted agents, such as anti-VEGFR inhibitors (sorafenib), multikinase SRC/ ABL1 inhibitors (dasatinib) as well as combinations with monoclonal antibodies (nimotuzumab); however, these combined approaches are yet to prove clinical efficacy [52,61,62]. 2.2.1.4

influence of endogenous angiogenesis inhibitors over angiogenic stimuli, although in solid tumors the regulation of both vascular proliferation and permeability is disrupted which leads to the so-called angiogenic switch. Tumorassociated angiogenesis is a complex process involving a number of proangiogenic factors that stimulate the proliferation and migration of endothelial cells. Among these molecules, the VEGF, the platelet-derived growth factor (PDGF) and basic fibroblast growth factor signaling appear to be the major inducers of angiogenesis, which are secreted in almost all kinds of cancer and tumor-associated stroma [63,64]. Angiogenesis as an attractive target in cancer therapy

2.2.2.1

Antiangiogenic TKIs Angiogenesis, the growth of new blood vessels, is an essential step in tumor growth and metastasis formation. In normal physiological circumstances, angiogenesis is tightly controlled, and vascular quiescence is maintained by the dominant 2.2.2

Following the recognition of the role of growth factor receptor pathways during epithelial carcinogenesis, a number of angiogenesis inhibitors have been developed with various binding capacities to angiogenic kinases (Table 3). According to their mechanisms of action, they can be divided in two


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Table 3. Selected angiogenesis inhibitors. Name

Phase of development

Monoclonal antibody Bevacizumab (Avastin)

VEGF

Approved for colorectal cancer (2004); NSCLC (2006), glioblastoma (2009) and RCC (2009)

TKIs Axitinib (Inlyta) Brivanib (BMS-582664) Cabozantinib (Cometriq) Cediranib (Recentin)

VEGFR, PDGFRB, KIT VEGFR2, FGFR VEGFR2, c-MET VEGFR, PDGFR-b, KIT

Approved for RCC (2012) Phase III HCC Approved for MTC (2012) Phase I/II/III for alveolar soft part sarcoma, glioblastoma Phase I/II ovarian, lung, NSCLC Phase II/IV RCC, stomach cancer, solid tumors

CP-547632 Dovitinib (TKI258) Expert Opin. Drug Discov. Downloaded from informahealthcare.com by EBSCO on 12/08/13 For personal use only.

Target

Foretinib (XL880) Motesanib (AMG706)

VEGFR2, FGFR VEGFR, PDGFR, FGFR, CSF1R, KIT, RET, FLT3 VEGFR, c-MET VEGFR, PDGFR-b, KIT, RET

Pazopanib (Votrient)

VEGFR, PDGFR-a/b, KIT

Regorafenib (Stivarga)

VEGFR, TIE-2, PDGFR, FGFR, KIT, RET, RAF VEGFR-2, KIT, FLT3, STAT-5, AKT

Semaxinib Sorafenib (Nexavar)

Telatinib (BAY57-9352)

VEGFR, EGFR, B-RAF, PDGFR, FLT3, KIT, RET VEGFR, PDGFR-a/b, FLT3, KIT, CSF1R, RET VEGFR2/3, PDGFR-b, KIT

Vandetanib (Caprelsa) Vatalanib (PTK787)

VEGFR2, EGFR, KIT, RET VEGFR, PDGFR-b, KIT

Inhibitors of mTOR Everolimus (Afinitor)

mTOR/PI3 kinase/AKT

Temsirolimus (Torisel)

mTOR/PI3 kinase/AKT

Sunitinib (Sutent)

main categories: compounds that bind to the ATP-binding site of the RTK and monoclonal antibodies that block the interaction of angiogenic ligands. An example is the monoclonal antibody bevacizumab (Avastin, Genentech/Roche) that specifically recognizes VEGF, thereby preventing interaction with its receptors [65]. Angiogenesis inhibitors Several antiangiogenesis TKIs as well as monoclonal antibodies are currently in clinical practice. Most notable antiangiogenic inhibitors target the VEGF-signaling pathway, namely sunitinib and sorafenib, which are used in the treatment of renal cell carcinoma (RCC), GIST and hepatocellular carcinoma (HCC) [65,66]. Semaxinib (SU5416), the first VEGFR TKI to be tested in humans, is a nonselective inhibitor of VEGFR-2, c-KIT and FLT-3. Initially, semaxinib showed promising results in a multicenter Phase II study in patients with refractory AML; however, randomized Phase II/III studies in solid tumors 2.2.2.2

8

Phase II (HCC and gastric tumor) GIST (imatinib-resistant), lung, thyroid, gall, bladder, breast, colorectal cancer Approved for RCC (2009) and soft tissue sarcoma (2012) Approved for metastatic colorectal cancer (2012) Phase II/II in AML, solid tumors, multiple myeloma; suspended Approved for renal cell and HCC (2007) Approved for GIST (2006), RCC (2006) and pancreatic neuroendocrine tumors (2011) Orphan drug status for advanced stomach cancer (2010); Phase II/III for other cancers Approved for MTC (2011) Phase I/III for solid tumors and melanoma Approved for RCC (2009), pancreatic neuroendocrine tumors (2011), subependymal giant cell astrocytoma (2010) and HER2-negative breast cancer (2012) Approved for RCC (2007), mantle cell/ non-Hodgkin’s lymphoma (European Union)

failed to show a survival benefit of semaxinib-containing regimens. Further, these studies showed severe drug toxicity such as increased risk of hematological, cardiovascular and thromboembolic events leading to the cessation of its further clinical development [1,65]. Sunitinib (Sutent, previously known as SU11248, Pfizer, Inc.) is a broad-spectrum small-molecule TKI of VEGFR, PDGFR, c-KIT, RET, CSF-1R and FLT-3 kinases, inhibiting angiogenesis and cell proliferation. In a multicenter Phase II clinical trial in metastatic renal cancer patients, 40% of the patients achieved a partial response and 27% demonstrated stable disease. Studies of sunitinib in a Phase III trial for imatinib-resistant GIST revealed a significantly longer time to progression in patients receiving sunitinib compared to patients on placebo leading to approval of sunitinib in 2006 for patients with metastatic RCC and imatinib-resistant GISTs [65-67]. Phase III clinical trials are ongoing in metastatic RCC using sunitinib versus interferon (IFN)-a as first-line treatment and in combination with chemotherapy [67-70].




Novel Phase II/III studies are investigating sunitinib in combination with erlotinib in patients with advanced, platinumrefractory NSCLC. It is hoped that targeting EGFR as well as VEGFR and PDGFR may increase its efficiency [71]. The third approved drug for treating GISTs is regorafenib (BAY 73-4506, Stivarga; Bayer HealthCare Pharmaceuticals, Inc.). Regorafenib is a multi-target inhibitor with a distinct antiangiogenic inhibition profile due to its dual VEGFR2-TIE2 TK inhibition. It also inhibits multiple receptor and intracellular kinases, including PDGFR-a/b, KIT, RET, FGFR1, BRAF and RAF-1. On February 2013, the approved use of regorafenib was expanded to treat patients with unresectable or metastatic GIST who no longer respond to other approved drugs (imatinib and sunitinib). Sorafenib (Nexavar, BAY 43-9006, Onyx Pharmaceuticals, Inc.) was originally developed as an inhibitor of the intracellular RAF kinase and subsequently it was found as an inhibitor of VEGFR, PDGFR-b and the serine/threonine RAF/MEK/ERK pathway. In 2005, it was approved for the treatment of patients with advanced RCC, and in 2007, it was approved for the treatment of unresectable HCC. Currently, clinical trials are evaluating the efficacy of sorafenib in combination with several chemotherapeutic and molecular targeted agents (erlotinib, gefitinib and bortezomib) in advanced solid tumors and leukemia [2,65,72,73]. Vatalanib (PTK787), which inhibits VEGFR, PDGFR and KIT, is currently being studied in Phase II/III trials in several types of cancer including previously treated patients with NSCLC and GIST [74].

(Zactima, ZD6474, AstraZeneca) is currently being used in patients with unresectable or metastatic MTC. Vandetanib targets several cell-surface receptors, such as SRC, VEGF, EGFR and RET, which is mutated in hereditary forms of MTC [78]. Despite the number of compounds in clinical trials, singleagent antiangiogenic therapies have yielded only modest effect on most cancer types. Initially, the majority of patients who have been treated with antiangiogenic inhibitors experienced an improvement in tumor response or disease stabilization. However, these benefits appear to be transient and ultimately almost all patients develop resistance to the drug. While some of the patients show intrinsic resistance, drug resistance often arises during antiangiogenic therapy [1,2,65]. One possible mechanism of acquired resistance is a specific secondary mutation in the target kinase resulting in a loss of inhibition. Acquired resistance may also be a consequence of the overexpression of a kinase which is not targeted initially. Alternatively, activation of parallel angiogenic pathways may overcome inhibition by a specific inhibitor. For example, the Delta-like 4/Notch signaling represents a parallel angiogenic pathway and its activation may overcome anti-VEGFR inhibitor therapies. Similarly, the PI3K/Akt pathway may be activated by angiopoietin-Tie signaling and may contribute to the escape mechanisms from antiangiogenic therapy [2,79,80]. It is likely that resistance in a given cancer is complex and may be caused by several resistance mechanisms due to interactive nature of angiogenic pathways. Multi-targeted inhibitors and combining inhibitors To overcome treatment resistance as well as to maximize antitumor effects of angiogenesis inhibitors, drug combinations have been proposed. Currently available or newly created antiangiogenic TKIs can be variously combined (Figure 2). Simultaneous administration of antiangiogenic and cytotoxic chemotherapy has resulted in proven activity in many cancers [2,65]. A second strategy is inhibition of multiple pathways with a cocktail of compounds that are directed against multiple tumor targets. For example, combining small-molecule TKIs that inhibit various receptors, such as VEGFR, PDGFR and EGFR, result in simultaneous inhibition of multiple pathways. Alternatively, combining small-molecule TKIs with an anti-VEGF monoclonal antibody (bevacizumab) may provide a synergistic effect [81-83]. A potential disadvantage of multi-target agents and combined therapies is the possibility that they will induce more toxicities as well, particularly when antiangiogenic agents are combined with chemotherapy. A number of clinical toxicities are observed during the use of antiangiogenic medications varying from common side effects, such as diarrhea or vomiting, to specific toxicities, such as nephrotic syndrome and hand-foot syndrome. Other common adverse effects include hypertension, renal vascular injury, gastrointestinal perforation and wound-healing problems (Table 4). Another important concern is the lack of adequate knowledge of 2.2.2.4

2.2.2.3

Novel multi-targeted agents

Cediranib, cabozantinib, pazopanib, vandetanib and motesanib are examples of recent TKIs that are approved or are currently in clinical trials for a variety of cancers. These compounds were developed to simultaneously target multiple regulatory molecules at the same time, and therefore may offer advantages over single-target agents. Most of these agents inhibit receptors, such as VEGFR and EGFR, and some also inhibit PDGFR, RAF and KIT. Targeting a cascade of key pathways may result in enhanced inhibition, thus representing a new opportunity for the treatment of patients resistant to previous therapies [65]. Cabozantinib (Cometriq, formerly known as XL184, AstraZeneca Pharmaceuticals) was approved in 2012 for the treatment of patients with progressive metastatic medullary thyroid cancer (MTC) [75]. Pazopanib (Votrient, GW78 6034, GlaxoSmithKline) is used in patients with advanced soft tissue sarcoma and is currently in Phase II/III trials for advanced NSCLC and RCC as a monotherapy or in combination with chemotherapy (paclitaxel and pemetrexed) [76]. Axitinib (Inlyta, AG013736, Pfizer, Inc.) was approved in 2012 for use in patients with advanced RCC, resistant to previous therapies. Phase III trials of axitinib versus sorafenib in advanced solid tumors, such as NSCLC and recurrent glioblastoma, are underway [77]. Another drug, vandetanib


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VEGF Monoclonal antibodies Bevacizumab

VGFR


Tyrosine kinase inhibitors Axitinib Cabozantinib Pazopanib Regorafenib Sorafenib Sunitinib Vandetanib

Vascular endothelial cell P

P

P

P

Tipifarnib Lonafarnib

RAS

Tipifarnib Ionofarnib Wortmannin

PI3K

FARA-A

AKT/PKB

RAF

PKC

Everolimus Temsirolimus

Cell survival

MEK

SPK

mTOR

Vascular permeability

Angiogenesis

Sorafenib Vemurafenib

Selumetinib Trametinib

ERK

Cell proliferation

Cell migration

Figure 2. A selection of signal transduction pathways blocked by monoclonal antibodies and TKIs that target the VEGFR TK families are shown. The activity of VEGFR can be inhibited either by blocking the extracellular ligand-binding domain with the use of anti-VEGFR antibodies, such as bevacizumab, or small molecules that inhibit the activity of the VEGFR TK, thus blocking the signaling pathways that are important in cell proliferation, invasion/metastasis, angiogenesis and cell survival. Approved VEGFR TKIs are showed in bold. Additionally, VEGFR inhibitors may also be combined with several other compounds of downstream components to increase treatment efficacy and to overcome drug resistance. Adapted in part from [65] with permission of John Wiley & Sons. Inspired by [79] and [98]. MEK MAPK and ERK: Extracellular-signal-regulated kinase (ERK) kinase; MEK: MAPK/ERK; mTOR: Mammalian target of rapamycin; PI3K: Phosphatidylinositol 3¢-kinase; PKB: Akt/protein kinase B; PKC: Protein kinase C; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; RAF, SPK, ‘P’ represent phosphate, which transduces the signal.

overlapping toxicities and the possibility of long-term toxicity of these compounds in patients with prolonged periods of therapy [84-87]. 3.

Conclusion

The success of small-molecule inhibitors in CML therapy illustrates that inhibition of TK activity is a validated therapeutic approach in oncology. However, it appears that currently administrated TKIs have limited activity in patients with advanced tumors receiving multiple therapies, to which their cancer has already developed resistance. It is certainly difficult to speculate, but it is unlikely that any of the compounds on the horizon can be a single magic bullet that 10

can address this heterogeneous, difficult-to-treat patient population. The future of targeted therapy lies in more personalized approach to care, where treatment is based on individual molecular profile of each person’s tumor. But to date, despite the huge effort and resources being spent, only a handful of validated target has been identified in solid tumors. Even when the target is identified, for example EGFR-activating mutation in a lung cancer patient, it may not be absolutely necessary a key driver molecular lesion that is necessary for tumor maintenance. This is particularly true in patients with late-stage disease who display unique combination of mutations and unstable genomes. And as we have seen, despite the availability of EGFR-targeted cancer therapies, current



Table 4. Toxicities observed during treatment with anti-EGFR and antiangiogenic TKIs. Toxicities with EGFR TKIs General Hematological Gastrointestinal Others Toxicities with antiangiogenic TKIs General Hematological


Gastrointestinal Cardiac and vascular Renal Central nervous system Others

Hair changes and alopecia, nail changes, hand and foot reactions, xerosis Neutropenia and anemia Nausea, diarrhea, vomiting, stomatitis and mucositis Maculopustular rash, asthenia, dyspnea, interstitial lung disease, ocular abnormalities, hypocalcemia hyperbilirubinemia and hypomagnesemia Fatigue, swelling, taste changes and skin pigmentation changes Leukopenia, myelosuppression, changes in hemoglobin levels, neutropenia, thrombocytopenia and immunomodulation Nausea, diarrhea, vomiting, abdominal pain and gastrointestinal perforation Hypertension, cardiac impairment, heart failure, thrombotic events, severe bleeding and disturbed wound healing Proteinuria, edema, thrombotic microangiopathy and nephrotic syndrome Dizziness, reversible posterior leukoencephalopathy syndrome and ataxia Hypothyroidism, loss of skeletal muscle mass, endocrine dysfunctions and hand-foot syndrome

anti-EGFR agents have yielded only modest effect on most cancer types. One of the steps in personalized medicine may be the identification of a novel molecular target and the approval of crizotinib (Xalkori, Pfizer, Inc.) for patients with locally advanced or metastatic NSCLC that is anaplastic lymphoma kinase (ALK)-positive [88]. Genetic alterations of ALK have been found in several cancers including anaplastic large cell lymphomas, neuroblastoma and NSCLC. ALK is usually dysregulated as a result of a chromosomal rearrangement leading to a creation of a fusion gene, which is presumed to be an oncogenic driver in these tumors. About 5% of all NSCLCs present the inv(2)(p21p23) rearrangement that generates the EML4/ALK fusion gene, which is used as a marker to select patients for crizotinib. The identification of ALK-rearranged fusion genes in solid tumors proves that gene fusion may be an important event in the development of common cancers. Discovering such rearrangements in solid tumors may lead to identification of molecular markers that can be specifically targeted. As the essence of any cancer therapy is that the best results are obtained when therapy is begun in the early stages of the disease, the obvious goal is to identify early genetic events critical in disease pathogenesis. The availability of a myriad of compounds and hundreds of clinical trials introduce a new challenge in cancer therapy. Therefore, new strategy is needed to optimize the use of targeted compounds to achieve the best respond rate while minimizing treatment toxicity in patients. 4.

Expert opinion

The use of TKIs in cancer therapy has resulted in proven activity across various tumor types. However, despite its well-established importance in cancer therapy, currently used TKIs show only modest effect on most cancer types. In patients with advanced tumors, single-agent TKI therapy has a narrow therapeutic index. In addition, the majority of these

responses are just palliative as well as often unpredictable. Unfortunately, a significant number of patients fail to achieve even initial responses or improvements in survival with currently available TKIs. Most often, clinical benefit is limited only to a fraction of patients (e.g., in EGFR-mutant adenocarcinoma or GISTs with c-KIT mutations), but complete responses are rare and ultimately almost all patients progress during therapy. Acquired resistance is a common feature in initial responders and the question whether novel drugs would overcome resistance is yet to be answered. Similarly, initial clinical data have shown only modest efficacy with combined approaches such as combination of single- or multi-target agents with monoclonal antibodies or with chemotherapy. While multi-targeted TKIs and combined therapies may provide advantages over agents with single targets, currently it is unknown whether these strategies will be able to overcome drug resistance and whether ultimately it will improve patient’s survival. Of course, one should realize that drug combinations and therapy with multi-targeted TKIs may result in overlapping severe toxicities as well. In contrast to initial expectations, just a few years ago -- that molecularly designed compounds would not only be more efficacious but also be with fewer side effects -- it is already obvious that combination of different compounds and/or therapies could cause more toxicity. There is also a major concern that multi-targeted TKIs may be associated with inhibition of other kinases, resulting in off-target toxicities and a spectrum of unexpected side effects that may impact treatment compliance. For example, inhibition of EGFRs has been linked to hypertension, pulmonary toxicity and maculopustular rash, whereas refractory hypertension, thromboembolic events, skin changes and hand-foot syndrome are common with VEGF inhibitors. These disappointing outcomes are in part due to the presence of various mutations and multiple aberrant signaling pathways in solid tumors. With the exception of a few malignancies, seemingly caused by a single genetic alteration, solid


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tumors are highly complex and heterogeneous. Recent global mutational analyses have revealed that human cancers are much more complex than it was previously imagined. They demonstrated that within a given tumor type there are a few frequently mutated gene ‘mountains’ and much more infrequently mutated gene ‘hills’. This incredible genetic heterogeneity was confirmed by recent pioneering studies of genomic landscapes of common human cancers, thus demonstrating that solid tumors contain many cell types both within individual tumor biopsies and spatially separated between biopsies of the same tumor [89-92]. But the problem is still more complicated. Tumor complexity is coupled with numerous overlapping protein interactions that occur between cancer cells and tumor microenvironment, between cancer cells and tumor vasculature and immune system and many more known and unknown interactions. These recent discoveries have been complicating the picture about cancer genome and have underscored the challenge in developing effective targeted therapies in solid tumors [90-95]. There are two fundamental problems in ‘cancer culture’ which may limit the success of targeted therapies: drug development strategies such as imperfect testing models and the rigidity of investigational drug trials. Today, when the entire healthcare system is moving toward the use of targeted drugs, large and small pharmaceutical companies are developing ‘promising’ compounds. Storming clinics with a myriad of compound may pose a challenge for health professional, who may face difficulties to choose the most effective therapy for an individual patient. A major challenge is also that contemporary clinical trials are slow and expensive, which are typically performed on very heterogeneous patient population, making it highly possible that a given drug could be effective. Thus, many potentially effective drugs might have worked well if investigational drug studies had been employed in highly selected patients who express specific molecular targets. In addition, most clinical trials test novel oncology agents on the sickest cancer patients, thus making it likely that the experimental compound makes little or no therapeutic benefit in advanced cancers with metastases. These trials have shown that many drugs could be effective in early stages of the disease when cancers are less heterogeneous and less aggressive. In support of this suggestion, our experience with targeted therapies in CML confirms that the major prognostic effect of TKIs can be achieved in early stage patients, while patients with advanced disease have been shown to be less sensitive to currently available therapies. Such a difference primarily reflects the inherent property of tumors in acquiring additional genetic changes that may originate from genomic instability. Genomic instability is a well-defined feature of CML, thus accumulation of multiple genomic lesions over time that result in genetically heterogeneous clones might explain therapy resistance to a single agent, particularly in advanced phases of CML.

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Therefore, in patients with advanced stage of diseases, combination therapies may turn out to be more effective. However, combining investigational compounds with a hope that it will work can be challenging and unlikely to prove successful. In addition to legal barriers and ethical issues in testing cocktails of unapproved drugs, a major challenge is also the choice of appropriate compounds in clinical trials. Thus, for the success of combinational therapies, it will be crucial to identify appropriate targets based on molecular profiles of selected patients. The one targeted drug that is clearly a success is imatinib mesylate that targets the oncogenic kinase activity of BCRABL1. The introduction of imatinib has resulted in outstanding clinical responses in CML patients and has fundamentally altered the pathobiology of a disease that was considered as incurable by chemotherapy and, therefore, fatal. CML patients on first- or second-generation TKIs can now expect to survive 10, 20 or more years. It is also likely, that after years of therapy, some of these patients will be considered as ‘cured’ and can stop the drug. In this regard, one of the most relevant issues is whether TKI therapy may be discontinued safely, at least in patients with durable absence of detectable BCRABL transcripts. According to the results of clinical studies, almost 50% of these patients who discontinued therapy did not relapse; however, imatinib cannot eradicate leukemia progenitor cells that may serve as a source for relapse in these patients. In contrast to imatinib, IFN-a targets CML primitive progenitors, and it has been demonstrated that administration of IFN-a after imatinib discontinuation may help to sustain durable remissions [96]. Owing to its remarkable activity and mild toxicity, imatinib has become the recommended initial treatment for CML patients throughout the world. A further success has been made when understanding the resistance mechanisms led to the development of new rationally designed drugs. Most recently, the third-generation TKI ponatinib and nonspecific (omacetaxine) therapies were approved to target imatinib-resistant mutants of BCR-ABL1, among others, the notoriously resistant T315I mutation. With the availability of a total of five kinase inhibitors for BCR-ABL1-expressing leukemia, the goal of cancer therapy for tailored treatment for individual patient (perhaps including an inhibitor of a resistant mutation) became realistic. To date, the success of TKIs in the treatment of BCR-ABL1+ leukemia remains the best example of successful targeted therapy [97]. Whether this success, to develop a specific drug for a specific cancer, will be the first example of future successes of targeted TKI therapy remains unclear.

Declaration of interest A Za´mecˇnı´kova declares that they have no conflict of interest and have received no payment in the preparation of their manuscript.




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15

Z. Adriana

Affiliation


Adriana Za´mecˇnı´kova Clinical Scientist, Cancer Geneticist, Kuwait Cancer Control Center, Department of Hematology, Laboratory of Cancer Genetics, PO Box 42262, 70653, Kuwait Tel: +00965 24821363; Fax: +00965 24810007; E-mail: [email protected]

16


Tyrosine kinase inhibitors in the treatment of prostate cancer: taking the next step in clinical development.

Fasting plus tyrosine kinase inhibitors in cancer.

Defining the role of tyrosine kinase inhibitors in early stage non-small cell lung cancer.

Mechanism of chemoresistance against tyrosine kinase inhibitors in malignant glioma.

Emerging tyrosine kinase inhibitors for the treatment of renal cancer.

The Fight Against Cervical Cancer.

Dendritic cell-based approaches in the fight against diseases.

Role of IGF-binding protein 3 in the resistance of EGFR mutant lung cancer cells to EGFR-tyrosine kinase inhibitors.

Tyrosine Kinase Inhibitors for the Elderly.

Tyrosine kinase inhibitors and pregnancy.

Tyrosine kinase inhibitors and interferon.

EGFR tyrosine kinase inhibitors in squamous cell lung cancer.

Biomarkers for tyrosine kinase inhibitors in renal cell cancer.

Melanoma-associated antigen expression and the efficacy of tyrosine kinase inhibitors in head and neck cancer.

Characterization of interactions and pharmacophore development for DFG-out inhibitors to RET tyrosine kinase.

[Advances and challenges in the fight against childhood cancer].

Effective virtual screening strategy focusing on the identification of novel Bruton's tyrosine kinase inhibitors.

Redundant kinase activation and resistance of EGFR-tyrosine kinase inhibitors.

Strategies to overcome resistance to tyrosine kinase inhibitors in non-small-cell lung cancer.

Growth factors and tyrosine kinase receptors during development and cancer.

Neu in the treatment of aggressive breast cancer.

Therapeutic drug monitoring and tyrosine kinase inhibitors.

Latest progress in tyrosine kinase inhibitors.

Cardiovascular Toxicities of Small Molecule Tyrosine Kinase Inhibitors: An Opportunity for Systems-Based Approaches.