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ScienceDirect Is target validation all we need? Melanie M Frigault and J Carl Barrett Targeted therapy for cancer treatment has required a shift in drug development approaches from broad treatment with chemotherapies, to the development of precision medicines that are specific for clinical targets. Cancer biology is widely studied and translating these findings into efficacious targeted therapies requires more than just target validation. Targets identified pre-clinically must be reproducible in other models that harbor the target. In addition, the extent and duration with which the target is modulated is at times essential for efficacy. Further, not only the target is of focus but also any inherent feedback mechanisms or mechanisms of acquired resistance should be understood to optimize chemistry of agents in development to target the tumor biology and to inform on combination approaches. Another element of a target that will likely contribute to successful clinical validation include the impact of target intra-tumor and inter-tumor heterogeneity on clinical efficacy. Taken together, to answer the question Is target validation all we need? We highlight a few elements of tumor biology and drug chemistry that if understood, may increase the successful clinical validation of new targets and therefore provide more targeted treatment options for this disease. Addresses Oncology Translational Science, AstraZeneca, Waltham, MA, USA Corresponding author: Barrett, J Carl ([email protected])

Current Opinion in Pharmacology 2014, 17:81–86 This review comes from a themed issue on Cancer Edited by Francisco Cruzalegui For a complete overview see the Issue and the Editorial Available online 27th September 2014 http://dx.doi.org/10.1016/j.coph.2014.09.004 1471-4892/# 2014 Elsevier Ltd. All right reserved.

Validation of a target in the clinic requires the development of a drug that selectively inhibits a specific target where the resultant clinical benefit is clear and recognized by regulatory authorities. In oncology, there are only 18 clinically validated targets that are approved (Table 1). In contrast, biopharmaceutical research companies are testing nearly 1000 medicines and vaccines against multiple types of cancer [1,2]. The Cancer Gene Census reports 513 genes that are potential targets [3]. Most of the clinically validated targets are genes that are mutated in various cancers, and even www.sciencedirect.com

though recent comprehensive genomic analyses across cancer types have identified 127–140 highly mutated cancer genes, the number of validated targets remains small ([4,5], and comment in [6]). With the wealth of knowledge from medical research to understand cancer and the enormous efforts from biopharmaceutical companies, we might have expected many more clinically validated cancer targets for effective cancer drugs. So why is it that there are so few clinically validated targets? The numbers speak for themselves, where research efforts in academia and industry continuously identifies numerous putative cellular drug targets, yet these rarely translate to approved medicines for cancer patients. Only 5% of pre-clinical therapies that begin testing in Phase 1 clinical trials progress through Phase 2/3 to become approved medicines for the treatment of cancer [7]. In addition, there are continued efforts for designing drugs for previously validated targets to make improvements for patient outcomes. For example, the treatment of HER2+ breast cancer continues to be active in clinical research even though HER2 is a validated target with approved therapies (Table 1). The community aims to optimize the sequence of HER2 targeted therapies, to determine the most beneficial combination approaches, to understand the best course of treatment for refractory HER2+ breast cancer, and to understand the mechanisms of acquired resistance to therapies [8]. In addition, new validated targets are arising from the design of next generation drugs for previously validated targets which are mutated and lead to acquired resistance, such as in lung cancer where new agents are developed for mutant non-small cell lung cancer (NSCLC) against altered forms of the validated targets EGFR and ALK [9]. Lessons learned can be gleamed from our knowledge of the development of validated targets (Table 1). Based on this collective experience, the field of clinical oncology may be able to apply best practices to improve attritions rates. Herein, we highlight some of the leanings from early drug discovery and clinical development. We propose that preclinical target identification, as well as target validation both pre-clinically and in the clinic are essential to the successful development of new drugs. In response to the question; Is target validation all we need? The answer is no and we discuss additional factors to consider in order to optimize the path from preclinical target validation to the development of new drugs for the treatment of cancer. We focus not only on the target itself, but highlight the need to consider the extent and duration with which the target is modulated, feedback mechanisms that arise as a Current Opinion in Pharmacology 2014, 17:81–86

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result of hitting the target, and the mechanisms with which resistance is acquired to a drug. In summary, not only the target, but the chemistry of the drug that modulates the target, as well as the biology of the disease must be understood.

Identification of targets Approaches to identifying targets have recently been reviewed elsewhere [10] where the target is either over expressed or abrogated by computational, genetic or biochemical methods to determine its causal role in cancer biology. In addition to these approaches, understanding the prevalence of the target in disease relevant tissues can point to putative targets with greater clinical relevance that can cell lines, and lead to an increased translatability from the benchside to the clinic [11].

Reproducibility of target validation The development of new drugs for the treatment of disease begins with the identification of a potential target. Biopharmaceutical research companies create drug candidates internally and often base target selection on scientific findings published from research institutions. The impact of identifying targets from the literature on drug development is discussed elsewhere, however, briefly two pharmaceutical companies have published that they found a lack of reproducibility of targets identified from the literature when they tried to repeat in house the published findings. Bayer examined 67 reports and Amgen tried to reproduce data from 53 publications identifying targets from publications. Both found a lack of reproducibility of the literature reported data in 60–70% of cases [12,13]. Internal target identification efforts by companies are also often not reproduced.

Drug–target interaction Duration of target inhibition by drugs is a key factor is drug development success. Tyrosine kinases are often deregulated in cancer and are ‘druggable’ targets [14]. One such mechanism for kinase deregulation is chromosomal rearrangements. These have proved to be clinically validated targets and continue to be of focus for the discovery of novel targets (reviewed by [15]). One of the first clinically validated chromosomal rearrangement targets is BCR-ABL where ABL kinase is rendered constitutively activated and patients who harbor this rearrangement receive benefit from BCR-ABL kinase inhibitors. Dasatinib and Imatinib are both approved agents for the treatment of CML (Table 1). Dasatinib modulates the target for a short duration but with maximal inhibition which is in contrast to the action of Imatinib which provides a more sustained modulation of the target at a more modest extent. Both drugs however, result in the same clinical benefit for CML [16,17]. Current Opinion in Pharmacology 2014, 17:81–86

In contrast, it is has been demonstrated for other targets that the extent of target inhibition dictates whether or not clinical benefit is achieved. Such is the case for the BRAF gene which is frequently mutated in melanoma. Early studies with a drug developed by Plexxikon that was ultimately approved as Vemurafenib showed patients who had paired biopsies collected before their first dose of and again after 14 days of dosing showed the drug treatment achieved 50% inhibition of pERK, which was thought from pre-clinical studies to be sufficient for efficacy but did not translate to efficacy for melanoma patients in the clinic. Reformulation of compound as Vemurafenib delivered higher exposures of the drug resulting in greater than 80% p-ERK inhibition. A clear correlation between extent of pharmacodynamic biomarker modulation; p-ERK, with clinical response; tumor shrinkage, was observed in patients with BRAF mutant melanoma [18,19,20]. Targets BCR-ABL and mutant BRAF exemplify that each target may have different requirements for the extent and duration of target modulation necessary to deliver clinical efficacy and sufficient target inhibition is a key success factor for clinical efficacy. This highlights that lack of drug activity could be due to the drug chemistry rather than target validity. The drug-kinase interaction has proven to be a successful approach to target validation. Continued development of kinase and multi-kinase drugs are expanding the potential of a kinase as a drug target, however the limitations of poly-pharmacology kinase drugs can be the dose limiting toxicities that prevent achieving doses high enough in the clinic to modulate the target to the extent and duration necessary for efficacy [21]. In addition to kinases as targets, the potential use of protein signaling networks as the targets for new therapeutic intervention is being interrogated with new drug chemistry approaches and more proteomic analyses to identify signaling nodes as targets [22].

Cancer biology beyond the target: no target is an island Analyses of tumor specimens from the clinic using next generation sequencing (NGS) have demonstrated the diversity of co-occurring gene lesions, including mutations, gene copy number variants and chromosomal rearrangements [30]. It is unclear whether these co-occurring genetic aberrations are drivers or passengers for the progression of the disease. As above, mutant BRAF is a validated target for the treatment of melanoma. However, Vemurafenib treatment of BRAF mutant colorectal cancer (CRC) is surprisingly not as effective as in melanoma [23,24]. In fact, in vitro studies have shown that decreases in p-ERK is not sustained in Vemurafenib treated CRC cell lines. It is the rapid re-activation of p-ERK by EGFR-RAS-CRAF that is demonstrated to provide the inherent resistance to BRAF inhibition in CRC. Combination with EGFR inhibitors blocks p-ERK www.sciencedirect.com

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Table 1 Current list of 18 FDA approved agents with a validated target. FDA approved indications are listed for each approved agent. Validated target 1

Agent(s) ABL

Imatinib (Gleevec), Bosutinib (Bosulif), Nilotinib (Tasigna) Dasatinib (Sprycel)

Ponatinib (Iclusig) a

FDA-approved indication(s) Chronic myelogenous leukemia (Philadelphia chromosome positive) Chronic myelogenous leukemia (Philadelphia chromosome positive), Acute lymphoblastic leukemia (Philadelphia chromosome positive) Chronic myelogenous leukemia, Acute lymphoblastic leukemia (Philadelphia chromosome positive)

2

ALK

Ceritinib (Zykadia) Crizotinib (Xalkori) b

Non-small cell lung cancer (with ALK fusion) Non-small cell lung cancer (with ALK fusion)

3

BRAF

Dabrafenib (Tafinlar) Vemurafenib (Zelboraf)

Melanoma (with BRAF V600E/K mutation) Melanoma (with BRAF V600E/K mutation)

4

BTK

Ibrutinib (Imbruvica)

Mantle cell lymphoma, Chronic lymphocytic leukemia

5

CD20

Ibritumomab tiuxetan (Zevalin), Tositumomab (Bexxar) Obinutuzumab (Gazyva), Ofatumumab (Arzerra, HuMax-CD20) Rituximab (Rituxan, Mabthera)

Non-Hodgkin’s lymphoma Chronic lymphocytic leukemia Non-Hodgkin’s lymphoma, Chronic lymphocytic leukemia

6 7

CD52 CTLA-4

Alemtuzumab (Campath) Ipilimumab (Yervoy)

B-cell chronic lymphocytic leukemia Melanoma

8

EGFR

Afatinib (Gilotrif) c

Non-small cell lung cancer (with EGFR exon 19 deletions or exon 21 substitution L858R mutations) Colorectal cancer (KRAS wild type), Squamous cell cancer of the head and neck Non-small cell lung cancer, Pancreatic cancer Non-small cell lung cancer Colorectal cancer (KRAS wild type)

Cetuximab (Erbitux) Erlotinib (Tarceva) Gefitinib (Iressa) Panitumumab (Vectibix) 9

HDAC

Romidepsin (Istodax) Vorinostat (Zolinza)

10

HER2

Lapatinib (Tykerb) d Trastuzumab (Herceptin) Ado-trastuzumab emtansine (Kadcyla), Pertuzumab (Perjeta)

11

KIT

Imatinib (Gleevec) e

Cutaneous T-cell lymphoma, Peripheral T-cell lymphoma Cutaneous T-cell lymphoma Breast cancer (HER2+) Breast cancer (HER2+), Gastric cancer (HER2+) Breast cancer (HER2+)

Regorafenib (Stivarga) f

GI stromal tumor (KIT+), Multiple hematologic malignancies including Philadelphia chromosome-positive ALL and CML Gastrointestinal stromal tumors

12

MEK

Trametinib (Mekinist)

Melanoma (with BRAF V600 mutation)

13

mTOR

Everolimus (Afinitor)

Temsirolimus (Torisel)

Pancreatic neuroendocrine tumor, Renal cell carcinoma, Nonresectable subependymal giant cell astrocytoma associated with tuberous sclerosis, Breast cancer (HR+, HER2 ) Renal cell carcinoma

14

RET

Cabozantinib (Cometriq) g Vandetanib (Caprelsa) h

Medullary thyroid cancer Medullary thyroid cancer

15 16

Smoothened RANKL

Vismodegib (Erivedge) i Denosumab (Xgeva)

Basal cell carcinoma Giant cell tumor of the bone

17

VEGF ligand

Bevacizumab (Avastin)

Colorectal cancer, Glioblastoma, Non-small cell lung cancer, renal cell carcinoma Colorectal cancer

Ziv-aflibercept (Zaltrap) j

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Table 1 (Continued ) Validated target 18

Agent(s) VEGFR

Ramucirumab (Cyramza) Axitinib (Inlyta) k Pazopanib (Votrient) l Regorafenib (Stivarga) m Sorafenib (Nexavar) n

FDA-approved indication(s) Gastric cancer or Gastroesophageal junction (GEJ) adenocarcinoma Renal cell carcinoma Renal cell carcinoma Colorectal cancer Hepatocellular carcinoma, Renal cell carcinoma, Thyroid carcinoma

a

Ponatinib has additional drug target activity to FGFR1-3, FLT3 and VEGFR2. Crizotinib is approved for ALK fusion NSCLC, and has additional drug target activity to MET. c Afatinib is approved for EGFR mutant NSCLC, and has additional drug target activity to HER2. d Lapatinib is approved for HER2+ Breast cancer, and has additional drug target activity to EGFR. e Imatinib is approved for KIT+ GIST, and has additional drug activity to PDGFR and ABL. f Regorafenib has additional drug activity to PDGFRb, RAF, RET and VEGFR1/2/3. g Cabozantinib has additional drug target activity to FLT3, KIT, MET, and VEGFR2. h Vandetanib has additional drug target activity to EGFR and VEGFR2. i Vismodegib has additional drug activity to PTCH. j Ziv-aflibercept has additional drug target activity to PIGF. k Axitinib also has drug target activity to PDGFRb and KIT. l Pazopanib has additional drug target activity to PDGFR and KIT. m Regorafenib has additional drug activity to KIT, PDGFRb, RAF and RET. n Sorafenib has additional drug target activity to PDGFR, KIT and RAF. b

reactivation and provides pre-clinical efficacy in vitro and in vivo [25]. Clinical trial combinations are ongoing to evaluate the efficacy of this combination for BRAF mutant CRC. Understanding the complexity of co-occurring deregulated genes/pathways in the biological context of the disease will elucidate any inherent feedback mechanisms surrounding a target and can inform combination approaches to achieve clinical benefit. Inherent to tumorigenesis is the adaptation of cancer cells to selective pressure. Although targeted therapies can provide some benefit, the duration of this benefit is limited due to the emergence of acquired resistance. Mechanisms of resistance can arise by alterations in the target itself which often abrogates drug binding, or in a by-pass manner where other pathways are activated making the target pathway redundant [26]. Understanding mechanisms of resistance allow the design of next generation targeted therapies or combination approaches to continue to target the primary target as well as the target emerging as a mechanism of resistance. EGFR mutant NSCLC is effectively treated with tyrosine kinase inhibitors (TKIs) of EGFR such as Gefitinib and Erlotinib (Table 1). Inevitably, however tumors stop responding to the drug and patients relapse. By collecting fresh biopsies at time of relapse, the molecular mechanism with which this tumor regrowth occurs is elucidated and second line treatments can be tested in clinical trials. EGFR TKI relapse NSCLC can arise with a mutation in EGFR where a T790M substitution abrogates binding of reversible EGFR inhibitors to the target. Next generation drugs that target both the primary EGFR mutation and the T790M forms that emerge from TKI relapse are being tested in the clinic. Also, combination approaches that target the emergent EGFR by-pass mechanisms of resistance where another Current Opinion in Pharmacology 2014, 17:81–86

tyrosine kinase, MET, is amplified are also being tested in the clinic (reviewed in [9]). There are some additional factors that merit consideration when deciphering the validation of targets, new and old. The intra patient and intra tumor variability of the expression of the target may also have an impact on efficacy. Cancer has long been described to be a clonal disease. The clonal hypothesis is supported by the observation that not all cancer cells in a tumor mass homogenously express the target. There are regions of the tumor that express the activated target and some that do not. Such is the case for mutations in the PIK3CA gene [27] and also for other genes using large NGS based approaches [28,29]. These studies have shown that if a single tumor sample is split into numerous sections and each section analyzed individually for the presence of gene mutations, not all sections will be identical. Will a targeted therapy be effective if the target is expressed in only a minor proportion of the tumor?

Target validation going forward In this article, we attempted to illustrate that target validation is necessary but not sufficient for successful drug development. Drugs can fail due to chemistry, that is, the failure of the drug to hit the target hard enough for efficacy, or the drug hits other targets leading to increasing toxicity. Also, the biology of cancer is complex with multiple drivers and acquired or adaptive resistant mechanisms emerge. In order to successfully develop novel targets to expand the clinical toolkit for the treatment of cancer, a better understanding of cancer biology and dynamics of the effect of target modulation is necessary. Taken together with reproducible target validation and establishing if the target is required or sufficient for www.sciencedirect.com

Is target validation all we need? Frigault and Barrett 85

tumorigenesis, we propose that all these elements will be necessary to reduce attrition rates and move putative targets and combination therapies through successful clinical trials.

Conflicts of interest statement Nothing declared.

References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:  of special interest  of outstanding interest 1.

PhRMA report: Medicines in Development — Cancer; published May 31, 2012 (http://www.phrma.org/sites/default/files/pdf/ phrmamedicinesindevelopmentcancer2012.pdf).

2.

Poste G: Bring on the biomarkers. Nature 2011, 469:156-157.

3. 

Futreal PA, Coin L, Marshall M, Down T, Hubbard T, Wooster R, Rahman N, Stratton MRMR: A census of human cancer genes. Nat Rev Cancer 2004, 4:177-183. This review demonstrates that multiple genes can be deregulated from sequencing data from human cancer genomes. Further, these can be many or few, and some mutations may be drivers while others passengers for tumorigenesis. 4.

Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, Leiserson MDM, Miller CA, Welch JS, Walter MJ, Wendl MC, Ley TJ, Wilson RK, Raphael BJ, Ding L: Mutational landscape and significance across 12 major cancer types. Nature 2013, 502:333-339.

5.

Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW: Cancer genome landscapes. Science 2013, 339:1546-1558.

6.

Workman P, Al-Lazikani B: Drugging cancer genomes. Nat Drug Discov 2013, 12:889-890.

7. Kola I, Landis J: Can the pharmaceutical industry reduce  attrition rates? Nat Rev Drug Discov 2004, 3:711-716. This perspectives from the authors points to the staggering rates of drug programs failures at various stages of development, but in particular that the attrition rates are most high in Oncology compared to other therapeutic areas. 8.

Singh JC, Jhaveri K, Esteva FJ: HER2-positive advanced breast cancer: optimizing patient outcomes and opportunities for drug development. Br J Cancer 2014 http://dx.doi.org/10.1038/ bjc.2014.388. (in press. Online publication 15 July).

9.

Camidge DR, Pao W, Sequist LV: Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol 2014, 11:473-481.

10. Schenone M, Dancˇı´k V, Wagner BK, Clemons PA: Target identification and mechanism of action in chemical biology and drug discovery. Nat Chem Biol 2013, 9:232-240. 11. Kauselmann G, Dopazo A, Link W: Identification of diseaserelevant genes for molecularly-targeted drug discovery. Curr Cancer Drug Targets 2012, 12:1-13. 12. Prinz F, Schlange T, Asadullah K: Believe it or not: how much can  we rely on published data on potential drug targets? Nat Rev Drug Discov 2011, 10:712. In a correspondence the authors share their ‘negative’ data where targets pulled from leading publications for new target identification for the development of new targeted agents. The article entitled ‘Believe it or not’, pointed out to the community that pre-clinical findings to commence drug programs at Bayer where seldomly reproducible. 13. Begley CG, Ellis LM: Drug development: raise standards for preclinical cancer research. Nature 2012, 483:531-533. 14. Mortlock A, Foote K, Kettle J, Aquila B: Kinase inhibitors in cancer. Reference module in chemistry. Mol Sci Chem Eng 2014 http://dx.doi.org/10.1016/B978-0-12-409547-2.11033-9. www.sciencedirect.com

15. Shaw AT, Hsu PP, Awad MM, Engelman JA: Tyrosine kinase gene rearrangements in epithelial malignancies. Nat Rev Cancer 2013, 13:772-787. 16. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL: Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001, 344:1031-1037. 17. Shah NP, Kim DW, Kantarjian H, Rousselot P, Llacer PE, Enrico A, Vela-Ojeda J, Silver RT, Khoury HJ, Mu¨ller MC, Lambert A, Matloub Y, Hochhaus A: Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica 2010, 95:232-240. 18. Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W,  Zhang C, Zhang Y, Habets G, Burton EA, Wong B, Tsang G, West BL, Powell B, Shellooe R, Marimuthu A, Nguyen H, Zhang KYJ, Artis DR, Schlessinger J, Su F, Higgins B, Iyer R, D’Andrea K, Koehler A, Stumm M, Lin PS, Lee RJ, Grippo J, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, Chapman PB, Flaherty KT, Xu X, Nathanson KL, Nolop K: Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 2010, 467:596-599. Based on the clinical efficacy and fresh paired biopsies from Vemurafenib treated BRAF mutant melanoma patients, this article describes that near complete modulation of the target and downstream signaling pathway is required in order to achieve clinical efficacy. 19. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB: Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010, 363:809-819. 20. Bollag G, Tsai J, Zhang J, Zhang C, Ibrahim P, Nolop K, Hirth P: Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat Rev Drug Discov 2012, 11:873-886. 21. Knight ZA, Lin H, Shokat KM: Targeting the cancer kinome through polypharmacology. Nat Rev Cancer 2010, 10:130-137. 22. Pawson T, Linding R: Network medicine. FEBS Lett 2008, 582:1266-1270. 23. Kopetz S, Desai J, Chan E, Hecht JR, O’Dwyer PJ, Lee RJ, Nolop KBL: PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors. J Clin Oncol 2010, 28(Suppl.) (abstr 3534). 24. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R,  Zecchin D, Beijersbergen RL, Bardelli A, Bernards R: Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 2012, 483:100-103. This article demonstrates that a target in one indication is not always efficacious in another indication. The demonstration that a feedback loop to reactivation of EGFR in CRC treatment with a BRAF inhibitor Vemurafenib, highlights that the biological context of a target must be understood in order to achieve clinical validation. 25. Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP, Brown RD, Della Pelle P, Dias-Santagata D, Hung KE, Flaherty KT, Piris A, Wargo JA, Settleman J, MinoKenudson M, Engelman JA: EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov 2012, 2:227-235. 26. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG: Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 2013, 13:714-726. 27. Dupont JJ, Laenkholm AV, Knoop A, Ewertz M, Bandaru R, Liu W,  Hackl W, Barrett JC, Gardner H: PIK3CA mutations may be discordant between primary and corresponding metastatic disease in breast cancer. Clin Cancer Res 2011, 17:667-677. The data presented by the authors with a focus on PI3KCA mutation, demonstrates that not all parts of a tumor specimen homogenously carry the mutation. The impact of targets/biomarkers heterogeneity on clinical efficacy remains a concern and warrants monitoring. Current Opinion in Pharmacology 2014, 17:81–86

86 Cancer

28. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C: Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012, 366:883-892. 29. Yap TA, Gerlinger M, Futreal PA, Pusztai L, Swanton C: Intratumor heterogeneity: seeing the wood for the trees. Sci Transl Med 2012, 4:127ps10. 30. Stephens PJ 1, Tarpey PS, Davies H, Van Loo P, Greenman C, Wedge DC, Nik-Zainal S, Martin S, Varela I, Bignell GR, Yates LR,

Current Opinion in Pharmacology 2014, 17:81–86

Papaemmanuil E, Beare D, Butler A, Cheverton A, Gamble J, Hinton J, Jia M, Jayakumar A, Jones D, Latimer C, Lau KW, McLaren S, McBride DJ, Menzies A, Mudie L, Raine K, Rad R, Chapman MS, Teague J, Easton D, Langerød A, Oslo Breast Cancer Consortium (OSBREAC), Lee MT, Shen CY, Tee BT, Huimin BW, Broeks A, Vargas AC, Turashvili G, Martens J, Fatima A, Miron P, Chin SF, Thomas G, Boyault S, Mariani O, Lakhani SR, van de Vijver M, van ‘t Veer L, Foekens J, Desmedt C, Sotiriou C, Tutt A, Caldas C, Reis-Filho JS, Aparicio SA, Salomon AV, Børresen-Dale AL, Richardson AL, Campbell PJ, Futreal PA, Stratton MR: The landscape of cancer genes and mutational processes in breast cancer. Nature 2012, 486:400404 http://dx.doi.org/10.1038/nature11017.

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Is target validation all we need?

Targeted therapy for cancer treatment has required a shift in drug development approaches from broad treatment with chemotherapies, to the development...
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