REVIEW URRENT C OPINION
The role of mitogen-activated protein targeting in melanoma beyond BRAFV600 Ryan J. Sullivan
Purpose of review Targeted therapy in melanoma is well established for patients with tumors harboring BRAFV600 mutations, but less so for other molecularly defined subsets. In this review, emerging preclinical, genomic, and early clinical data are discussed regarding the use of mitogen-activated protein (MAPK) pathway inhibitors in other molecular subsets of melanoma. Recent findings There are now four well defined subsets of melanoma based on The Cancer Genome Atlas: BRAF driven, NRAS driven, NF1 mutant, and ‘triple wild type’. The former three subtypes predict signaling through the MAPK pathway and sensitivity to inhibitors of this pathway’s mediators. With ongoing translation of preclinical findings into clinical trials, there is great hope that these strategies will improve the care of patients who fall into these other molecular subsets. Summary A more comprehensive understanding of genetically defined subtypes of melanoma is emerging. Efforts in the clinic are already underway, but additional, well designed trials of MAPK-targeted therapy planned and needed. Keywords ERK inhibitors, MEK inhibitors, NF1, NRAS, The Cancer Genome Atlas
INTRODUCTION The treatment of melanoma has been revolutionized. A mere decade ago, the treatment options for metastatic melanoma consisted of ineffective and toxic chemotherapy, highly toxic and rarely effective immunotherapy, or enrollment onto clinical trials, such as with the combination of chemotherapy and immunotherapy, that occasionally showed a promising safety signal in phase II trials that ultimately were proven no better than single-agent chemotherapy in randomized, phase III trials [1–3]. The era of chemotherapy which spanned from the mid-1940s until the early 2000s changed the way the world thought of cancer, from an always lethal, insidious killer to a powerful, yet vulnerable enemy that could be overcome with toxins that targeted the Achilles heel of dividing cells, in short the machinery that drives cell division. Although this approach saved the lives of countless leukemia, lymphoma, breast cancer, and testicular cancer patients, it was a wholly ineffective strategy for many solid tumor malignancies, and the great majority of patients with metastatic melanoma received no benefit when they were treated with chemotherapy. Over
the past two decades in the laboratory, a remarkable amount of effort has been placed into identifying the genetic factors driving tumor development and growth and in determining the elegant mechanisms of immune cell activation and regulation. In turn, the clinic has been a fertile space to translate these discoveries into meaningful treatment options for patients and, in melanoma, has directly led to a number of positive phase III trials that have led to the regulatory approval of eight new therapies, involving five distinct mechanisms of activity that include oncogene pathway inhibition targeting and immune cell activation [4–14]. As we look ahead to the next decade of drug development in this disease, it is expected that optimal sequencing and combinatorial regimens of approved agents will be Center for Melanoma, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA Correspondence to Ryan J. Sullivan, MD, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114, USA. Tel: +1 617 724 4400; e-mail: [email protected] Curr Opin Oncol 2016, 28:185–191 DOI:10.1097/CCO.0000000000000271
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KEY POINTS Recently published efforts from the melanoma TCGA have defined four molecular subsets of cutaneous melanoma: BRAF driven, NRAS driven, NF1 mutated, and ‘triple wild type.’ Most melanomas signal through the MAPK pathway, but there is emerging preclinical and clinical evidence that inhibitor of MAPK pathway mediators may be an effective strategy in many patients. Unfortunately, these strategies are unlikely to have the same success as MAPK inhibitor therapy in BRAFV600mutated melanoma, so further translational work will need to be done to figure out which patients are most likely to benefit and to sort out the mechanisms of resistance in those who did not benefit.
explored, as well as the identification of new targets and agents that might effectively engage and disrupt these targets. The great majority of melanomas harbor driving oncogenic mutations in either BRAF or NRAS, which leads to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway [15 ]. Targeting this pathway, particularly in patients with BRAF mutant melanoma, has led to major advances in the management of these patients, and has led to the approval of two BRAF inhibitors (dabrafenib and vemurafenib), two MEK inhibitors (trametinib and cobimetinib), and two BRAF/MEK inhibitor combinations (dabrafenib plus trametinib and vemurafenib plus cobimetinib) [4–6,8–10,12] (reviewed in [16]). As BRAF mutations only are seen in half of patients with melanoma, one of the unmet needs in our field is the development of effective, targeted therapy for patients without BRAF mutations. The focus of this review is just that, the description of the molecular underpinnings of BRAF wild-type melanoma and the strategies that have been taken, both preclinically and clinically, to target these. &&
LESSONS FROM THE CANCER GENOME ATLAS The Cancer Genome Atlas (TCGA) project is a remarkably comprehensive and informative endeavor that has aimed to molecularly characterize human cancer. The recent publication of the data in cutaneous melanoma has been a revelation. Although this dataset confirmed the presence of hotspot BRAF (50%) and NRAS (27%) mutations, two other molecular subsets were defined: NF1 subtype, which is mutated in 14% of cases, and the ‘triple wild type’ subtype, which is highlighted by a 186
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lack of BRAF, NRAS, and NF1 mutation [15 ]. As Fig. 1 depicts, the three genetically defined subclasses are predicted to activate the MAPK pathway, as too are various mutations that are identified in the triple wild-type subset, including mutations or amplifications of CKIT, PDGFRa amplification, KDR (VEGFR2) amplification, as well as mutations in the small g-protein a subunits GNAQ and GNA11. Moving beyond MAPK activating mutations, a number of other genomic aberrations are described. The most common is inactivating mutations/loss of CDKN2A, a key genetic regulator of cyclin-dependent kinase 4 (CDK4), cyclin D1 (CCND1), and the cell cycle (reviewed in [17]). CDK4 and CCND1, in turn, are critical regulators of retinoblastoma protein 1, which is a well known tumor suppressor gene that inhibits E2F, the final arbiter of cell cycle activation. Interestingly, CDKN2A is mutated, deleted, or hypomethylated across the four major molecular categories in 40–70% of cases. Additionally, CDK4 and CCND1 mutation or amplification is seen in a substantial minority of patients. And finally, retinoblastoma protein 1 is mutated/deleted in 10% of patients, particular those in the NF1 subset. The widespread nature of these genomic abnormalities suggests that cell cycle dysregulation is not only critical to melanoma development but also may serve as an important target for small molecule inhibition. Other abnormalities have been seen and include those in the phosphatidylinositol 3 kinase (PI3K)/ AKT pathway (including mutation/deletion of PTEN, AKT3 mutations/overexpression, and PIK3CA mutations) and DNA damage response and apoptosis pathways (TP53 mutations in 10–30%, depending on subset, MDM2 and MDM4 amplifications, and abnormalities of key inhibitors of apoptosis such as BCL2, BCL2L12, and MCL1). Additionally, mutations have also been shown to occur in genes related in epigenetic regulation in up to 30% of cases. These include ARID2, ARID1A, ARID1B, IDH1, and EZH2. Another important component of the TCGA was generated with RNA sequencing. The two major findings of this analysis were as follows: fusion events were regularly seen and might drive tumorigenesis and represent targets of small molecule inhibitors; gene expression profiling identified three subclasses, in which all tumors fell, called ‘immune’, ‘keratin’, and ‘MITF low’. Although specific information about how to therapeutically approach using targeted therapy based on this classification is not known, other than the strong hypothesis that immunotherapy may be a good choice for the ‘immune’-rich gene expression profile. Volume 28 Number 2 March 2016
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Role of mitogen-activated protein targeting in melanoma Sullivan
PDGFR2 CKIT
KDR VEGFR2
NRASGDP
GNAQ/11 NRASGTP
NF1
NRAS-mt RAF
HIPPO pathway
BRAF*
BRAFV600
Immune evasion MEK Cell survival
Invasion and metastasis
Cell cycle progression
ERK
FIGURE 1. Relevant signaling cascades in melanoma. Multiple mediators (in black) and regulators of the mitogen-activated protein pathways have been linked to melanoma. Key oncogenic driver mutations (light gray) include BRAFV600, NRAS (typically at either Q61, G12, or G13), GNAQ and GNA11 (typically in uveal melanoma), and less frequently CKIT, PDGFR2, and KDR/VEGFR2. The tumor suppressor gene NF1 (dark gray) regulates RAS activation.
IMPORTANCE OF THE MITOGENACTIVATED PROTEIN PATHWAY IN MELANOMA Independent of driving mutation status (e.g., BRAF, NRAS, and NF1), the MAPK pathway is nearly always activated in melanoma [18]. Further, the driving oncogenes in melanoma all signal through the pathway via constitutive activation of its key mediators. Canonical signaling pathway starts with cell surface receptor, either g-protein coupled receptor or receptor tyrosine kinase, engagement with ligand. With the activation of g-protein coupled receptor or receptor tyrosine kinase, RAS is activated by guanine nucleotide exchange factor-mediated conversion of RAS bound to guanosine diphosphate to RAS GTP (in either H, K, or N-isoforms) [19]. Of note, NF1 serves as a key regulator of RAS through GTPase-activating protein, which converts the active GTP-bound RAS to GDP-bound RAS [20]. Once in its active form, RAS is capable of interacting with a number of cell signaling mediators, but one of its most critical capabilities is to bind to the RASbinding domain on any of the RAF (A, B, or C) isoforms [21–24]. RAS binding triggers homo and heterodimerization and activation of RAF, a serine threonine kinase that then activates MEK via a phosphorylation event [21,23–26]. Once
activated, MEK1 mediates activation of ERK, which then leads to a number of downstream events including cell cycle activation (through CCND activation), and inhibition of apoptosis (through inhibition of proapoptotic BAD and BIM) [18]. A number of inhibitors of the MAPK pathway mediators have been or are currently under development including four drugs, the BRAF inhibitors vemurafenib and dabrafenib and MEK inhibitors trametinib and cobimetinib, that have been approved by the US Food and Drug Administration for the treatment of BRAF mutant-advanced melanoma, either as single agents (vemurafenib, dabrafenib, and trametinib) or in combination (dabrafenib plus trametinib and vemurafenib plus cobimetinib) [4–6,8–10,12]. Additionally, other RAF inhibitors, including sorafenib, encorafenib, XL281, and R05126766, MEK inhibitors, including selumetinib and binimetinib, and more recently an ERK inhibitor, ulixertinib, have been tested in various unselected and selected cohorts of melanoma patients [27–30,31 ,32–43]. Additional pan-BRAF, MEK, and ERK inhibitors are also under development and are likely to be tested in cohorts of patients with melanoma. What follows is a summary of the recent and current strategies to target the MAPK pathway in melanoma patients without BRAFV600 mutations.
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TARGETED THERAPY IN MITOGENACTIVATED PROTEIN-DRIVEN, MOLECULAR SUBSETS OF MELANOMA Targeting uveal melanoma Mutations in GNAQ and GNA11 are present in the great majority of uveal melanoma and predict signaling through the HIPPO pathway [44–47]. Further, upregulation of a number of signaling pathways including protein kinase C (PKC), MAPK, and PI3K pathways has been described, and preclinical evidence supports the use of inhibitors of MET, MEK, PKC, and PI3K/AKT/mTOR inhibitors, either as a single agent or in combination [48–52,53 ,54–56]. Clinically, single agent MEK inhibition has been an active area of investigation. For example, a randomized phase II trial of selumetinib vs. chemotherapy (either dacarbazine or temozolomide) in 120 patients with metastatic uveal melanoma showed that selumetinib was associated with an improved response rate (14 vs. 0%) and progression-free survival (15.9 vs. 7 weeks, hazard ratio 0.46, P < 0.001) compared with chemotherapy, but no statistically significant improvement in overall survival (11.8 vs. 9.1 months, hazard ratio 0.66, P ¼ 0.09) [31 ]. Disappointingly, a randomized phase III trial of selumetinib plus dacarbazine vs. dacarbazine plus placebo failed to show an improvement in progression-free survival or even an increase in responses in the experimental arm (Carvahal SMR 2015). Other MEK inhibitors have been tested, although not as extensively as selumetinib. For example, a randomized phase II trial of the MEK inhibitor trametinib and the AKT inhibitor GSK2141795 (NCT01979523) is currently enrolling. In addition, tumor reduction has been seen in uveal melanoma patients in the phase I trial of the pan-RAF inhibitor XL281 and in a phase I trial of trametinib plus the CDK4 inhibitor palbociclib [33,57]. Targeting PKC signaling with the PKC inhibitor AEB071, either as a single agent (NCT01430416) or in combination with a MEK inhibitor (NCT01801358) or PI3K inhibitor (NCT02273219), is another strategy being testing in the clinic. The single agent study showed rare responses in this patient population and has not been moved forward. The combination of AEB071 plus binimetinib was tested in a phase Ib trial and has been associated with significant toxicity limiting therapeutic exposure of both AEB071 and binimetinib. Other ongoing studies in this patient population include a number of MET inhibitor trials, including the randomized phase II trial in the Alliance intergroup comparing the MET inhibitor cabozantinib with chemotherapy (NCT01835145). This trial is based &
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on a phase II trial of cabozantinib in patients with melanoma that enrolled 15 patients with metastatic uveal melanoma, 10 of whom had a best response of stable disease and four of these patients were maintained progression free for over 6 months.
Targeting NRAS and NF1 mutant melanoma Activating mutations of NRAS are the second most common oncogenic mutations in melanoma and are present in 20–30% of patients associated with MAPK activation [15 ,58,59]. Mutations in NF1 are seen in a significant minority of patients and represent a third molecularly defined subgroup in melanoma, along with BRAF and NRAS mutant subsets [15 ,60,61 ]. These mutations are associated with inactivation of NF1, which leads to preferential RAS confirmation into GTP-bound, active RAS [60]. Interestingly, NF1 mutation does not always lead to RAS activation, as there is a wide range of the degree of RAS activation with NF1 loss. However, NF1-mutated melanomas are often comutated with so-called ‘RAS-opathy’ genes (which include RASA2, PTPN11, SOS1, RAF1, and SPRED1) that do predict increased RAS activation [61 ,62]. As the major ramification of either NRAS or NF1 mutation is the increased MAPK pathway signaling, targeting mediators of this pathway is logical and supported by preclinical evidence. In fact, pan-RAF inhibitors, MEK inhibitors, and ERK inhibitors all have substantial preclinical activity in NRAS mutant tumors [63–66]. Although there is more variability about how robustly NF1 mutations mediate MAPK activation, these tumors generally are vulnerable to MEK and ERK inhibition in vitro and in vivo [60,61 ]. In patients, the MEK inhibitor binimetinib is associated with a 20% response rate and 4.8-month progression-free survival in NRAS mutant patients [28]. Based on these data, a randomized phase III trial comparing binimetinib with dacarbazine is underway (NCT01763164), and if positive, would change the standard of care for this patient population. There is also a randomized phase II trial of the MEK inhibitor pimasertib compared with dacarbazine that has completed enrollment (NCT01693068). Responses also have been seen in NRAS mutant melanoma patients in the phase I trial of the RAF–MEK inhibitor R0512676, the pan-RAF inhibitor XL281, and in the phase I trial of the ERK inhibitor, ulixertinib. These agents, as well as the pan-RAF inhibitors LY3009120 and MLN2480, and the ERK inhibitor GDC-0994 would also be predicted to have clinical activity and actively are being studied in this patient population. To date, there &&
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have been no reports of activity or inactivity with any of these agents in NF1 mutant patients. Despite promising early clinical data, the majority of NRAS mutant melanoma patients either will not or will only transiently benefit from MEK inhibitors [28]. Thus, strategies to overcome either intrinsic or acquired resistance to MEK inhibitors are needed. In an elegant experiment, investigators (Kwong and colleagues) performed comparative analysis from NRAS mutant melanoma tumors treated with vehicle, MEK inhibitor, and NRAS extinction, determining that CDK4 was the top pathway regulator in the MEK treated but not NRAS extinction model [67]. The consequences of these findings are that CDK4 expression was predicted to mediate MEK inhibitor resistance in NRAS mutant melanoma. Next, the combination of MEK and CDK4/6 inhibitor therapy was compared with either agent alone and shown to be more effective in multiple NRAS xenograft models [67]. Building on this work, a phase I/II trial of the MEK inhibitor binimetinib in combination with the CDK4/6 inhibitor LEE011 in patients with metastatic NRAS mutant melanoma opened to enrollment and the preliminary data were presented at ASCO 2014 and updated at ECCO 2015 [68,69]. Tumor regression initially was seen in most patients across all dose cohorts, and responses were seen in seven of the 22 patients enrolled and another 11 had stable disease, though the response rate seems to be higher than originally described, 41% in the 22 patients enrolled at the 28-day schedule [69]. The results from a similar trial, one evaluating the combination of trametinib plus palbociclib for patients with all solid tumors, was recently reported [57] (NCT02065063). In this dose escalation study, only two responses were seen (one in an NRAS mutant colon cancer patient and the other in a NRAS/BRAF/NF1 wild-type melanoma patient) among the 26 patients treated. In the eight NRAS mutant patients, one responded (the aforementioned colon cancer patient), four had stable disease, and three had progression of disease as a best response. Two NF1 mutant patients were enrolled and both had transient stable disease.
Targeting non-BRAFV600, BRAF mutant melanoma Although the majority of BRAF mutations involve a substitution of valine for a glutamic acid at the 600 position, a number of other, non-V600 mutations have been described. Some, such as K601E and L597Q, lead to a constitutively active kinase and
are susceptible to MEK inhibition [70,71]. Others, including a wide range of mutations at various sites in the kinase domain, lead to a kinase dead state that facilitates heterodimerization with wild-type RAF species (A, B, or C) and activation of the pathway [72]. As preclinical and limited clinical evidence supports the use of MAPK inhibitors in this patient population, clinical trials are exploring the effectiveness of these strategies. In particular, a phase II trial of trametinib (NCT02296112) is specifically enrolling non-V600, BRAF mutant melanoma patients, and a number of phase I trials are targeting these patients in expansion cohorts (NCT01781429 and NCT02014116).
CONCLUSION Recently, large-scale genomic characterization efforts have identified four major subgroups of patients based on the dominant, MAPK-activating, tumor-promoting mutation: BRAF; NRAS; NF1; and triple wild type. With an expanding understanding of the genetic drivers of melanoma, effective therapies have been and will continue to be developed to treat a number of specific, molecularly defined subsets of patients. The most celebrated efforts to date have occurred in the BRAFV600 mutant subset, with four drugs and two drug combinations receiving regulatory approval in the past 4 years. Although this level of success has not been reached to date in other subsets, there is clear rationale for MAPK inhibitors in NRAS, NF1, non-V600 BRAF, and uveal melanoma that will be explored further. The most important efforts will be made in well designed preclinical studies that shed light into the mechanisms of both intrinsic and acquired resistance of single-agent therapy and identify promising combinations to be brought forward into the clinic. Additionally, it will be critical to perform serial biopsies in patients treated with single-agent MEK, pan-RAF, and ERK inhibitors to identify the pharmacodynamic effects of these agents on tumors and ideally to sort out the molecular determinants that predict which patients will benefit and to confirm mechanisms of resistance. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest R.J.S. has served as a consultant for Novartis Pharmaceuticals.
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Role of mitogen-activated protein targeting in melanoma Sullivan 49. Ambrosini G, Pratilas CA, Qin LX, et al. Identification of unique MEKdependent genes in GNAQ mutant uveal melanoma involved in cell growth, tumor cell invasion, and MEK resistance. Clin Cancer Res 2012; 18:3552– 3561. 50. Ho AL, Musi E, Ambrosini G, et al. Impact of combined mTOR and MEK inhibition in uveal melanoma is driven by tumor genotype. PloS One 2012; 7:e40439. 51. Musi E, Ambrosini G, de Stanchina E, Schwartz GK. The phosphoinositide 3-kinase alpha selective inhibitor BYL719 enhances the effect of the protein kinase C inhibitor AEB071 in GNAQ/GNA11-mutant uveal melanoma cells. Mol Cancer Ther 2014; 13:1044–1053. 52. Surriga O, Rajasekhar VK, Ambrosini G, et al. Crizotinib, a c-Met inhibitor, prevents metastasis in a metastatic uveal melanoma model. Mol Cancer Ther 2013; 12:2817–2826. 53. Chen X, Wu Q, Tan L, et al. Combined PKC and MEK inhibition in uveal & melanoma with GNAQ and GNA11 mutations. Oncogene 2014; 33:4724– 4734. Excellent article describing the preclinical rationale for an important, MEK inhibitorbased trial in uveal melanoma. 54. Sagoo MS, Harbour JW, Stebbing J, Bowcock AM. Combined PKC and MEK inhibition for treating metastatic uveal melanoma. Oncogene 2014; 33:4722–4723. 55. Chattopadhyay C, Grimm EA, Woodman SE. Simultaneous inhibition of the HGF/MET and Erk1/2 pathways affect uveal melanoma cell growth and migration. PLoS One 2014; 9:e83957. 56. von Euw E, Atefi M, Attar N, et al. Antitumor effects of the investigational selective MEK inhibitor TAK733 against cutaneous and uveal melanoma cell lines. Mol Cancer 2012; 11:22. 57. Phase 1b dose-escalation study of trametinib (MEKi) plus palbociclib (CDK4/6i) in patients with advanced solid tumors. Sullivan RJ, Amaria RN, Lawrence DP, et al., editors. Molecular Targets and Cancer Therapeutics. Boston, Massachusetts; 2015. 58. Hodis E, Watson IR, Kryukov GV, et al. A landscape of driver mutations in melanoma. Cell 2012; 150:251–263. 59. Omholt K, Platz A, Kanter L, et al. NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res 2003; 9:6483–6488. 60. Nissan MH, Pratilas CA, Jones AM, et al. Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence. Cancer Res 2014; 74:2340–2350.
61. Krauthammer M, Kong Y, Bacchiocchi A, et al. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nat Genet 2015; 47:996–1002. Wonderful, elegant study describing the role of NF1 alone or in cooperation with other ‘RASopathy genes’ in melanoma. This study also provides an analysis of both the Yale genomic efforts together, which at 213 patients analyzed represents the second largest data set behind the TCGA. 62. Arafeh R, Qutob N, Emmanuel R, et al. Recurrent inactivating RASA2 mutations in melanoma. Nat Genet 2015; 47:1408–1410. 63. Nakamura A, Arita T, Tsuchiya S, et al. Antitumor activity of the selective panRAF inhibitor TAK-632 in BRAF inhibitor-resistant melanoma. Cancer Res 2013; 73:7043–7055. 64. Okaniwa M, Hirose M, Arita T, et al. Discovery of a selective kinase inhibitor (TAK-632) targeting pan-RAF inhibition: design, synthesis, and biological evaluation of C-7-substituted 1,3-benzothiazole derivatives. J Med Chem 2013; 56:6478–6494. 65. Rebecca VW, Alicea GM, Paraiso KH, et al. Vertical inhibition of the MAPK pathway enhances therapeutic responses in NRAS-mutant melanoma. Pigment Cell Melanoma Res 2014; 27:1154–1158. 66. Wong DJ, Robert L, Atefi MS, et al. Antitumor activity of the ERK inhibitor SCH722984 against BRAF mutant, NRAS mutant and wild-type melanoma. Mol Cancer 2014; 13:194. 67. Kwong LN, Costello JC, Liu H, et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med 2012; 18:1503– 1510. 68. Sosman JA, Kittaneh M, Lolkema MPJK, et al., eds. A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRASmutant melanoma: Early encouraging clinical activity. ASCO Annual Meeting; 2014; Chicago, IL: J Clin Oncol. 69. Van Herpen C, Postow MA, Carlino MS, et al., eds. A phase 1b/2 study of ribociclib (LEE011; CDK4/6 inhibitor) in combination with binimetinib (MEK162; MEK inhibitor) in patients with NRAS-mutant melanoma. European Cancer Congress; 2015; Vienna, Austria. 70. Bowyer SE, Rao AD, Lyle M, et al. Activity of trametinib in K601E and L597Q BRAF mutation-positive metastatic melanoma. Melanoma Res 2014; 24:504– 508. 71. Dahlman KB, Xia J, Hutchinson K, et al. BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitors. Cancer Discov 2012; 2:791–797. 72. Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 2010; 140:209–221.
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The role of mitogen-activated protein targeting in melanoma beyond BRAFV600 Ryan J. Sullivan
Purpose of review Targeted therapy in melanoma is well established for patients with tumors harboring BRAFV600 mutations, but less so for other molecularly defined subsets. In this review, emerging preclinical, genomic, and early clinical data are discussed regarding the use of mitogen-activated protein (MAPK) pathway inhibitors in other molecular subsets of melanoma. Recent findings There are now four well defined subsets of melanoma based on The Cancer Genome Atlas: BRAF driven, NRAS driven, NF1 mutant, and ‘triple wild type’. The former three subtypes predict signaling through the MAPK pathway and sensitivity to inhibitors of this pathway’s mediators. With ongoing translation of preclinical findings into clinical trials, there is great hope that these strategies will improve the care of patients who fall into these other molecular subsets. Summary A more comprehensive understanding of genetically defined subtypes of melanoma is emerging. Efforts in the clinic are already underway, but additional, well designed trials of MAPK-targeted therapy planned and needed. Keywords ERK inhibitors, MEK inhibitors, NF1, NRAS, The Cancer Genome Atlas
INTRODUCTION The treatment of melanoma has been revolutionized. A mere decade ago, the treatment options for metastatic melanoma consisted of ineffective and toxic chemotherapy, highly toxic and rarely effective immunotherapy, or enrollment onto clinical trials, such as with the combination of chemotherapy and immunotherapy, that occasionally showed a promising safety signal in phase II trials that ultimately were proven no better than single-agent chemotherapy in randomized, phase III trials [1–3]. The era of chemotherapy which spanned from the mid-1940s until the early 2000s changed the way the world thought of cancer, from an always lethal, insidious killer to a powerful, yet vulnerable enemy that could be overcome with toxins that targeted the Achilles heel of dividing cells, in short the machinery that drives cell division. Although this approach saved the lives of countless leukemia, lymphoma, breast cancer, and testicular cancer patients, it was a wholly ineffective strategy for many solid tumor malignancies, and the great majority of patients with metastatic melanoma received no benefit when they were treated with chemotherapy. Over
the past two decades in the laboratory, a remarkable amount of effort has been placed into identifying the genetic factors driving tumor development and growth and in determining the elegant mechanisms of immune cell activation and regulation. In turn, the clinic has been a fertile space to translate these discoveries into meaningful treatment options for patients and, in melanoma, has directly led to a number of positive phase III trials that have led to the regulatory approval of eight new therapies, involving five distinct mechanisms of activity that include oncogene pathway inhibition targeting and immune cell activation [4–14]. As we look ahead to the next decade of drug development in this disease, it is expected that optimal sequencing and combinatorial regimens of approved agents will be Center for Melanoma, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA Correspondence to Ryan J. Sullivan, MD, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114, USA. Tel: +1 617 724 4400; e-mail: [email protected] Curr Opin Oncol 2016, 28:185–191 DOI:10.1097/CCO.0000000000000271
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Melanoma and other skin neoplasms &&
KEY POINTS Recently published efforts from the melanoma TCGA have defined four molecular subsets of cutaneous melanoma: BRAF driven, NRAS driven, NF1 mutated, and ‘triple wild type.’ Most melanomas signal through the MAPK pathway, but there is emerging preclinical and clinical evidence that inhibitor of MAPK pathway mediators may be an effective strategy in many patients. Unfortunately, these strategies are unlikely to have the same success as MAPK inhibitor therapy in BRAFV600mutated melanoma, so further translational work will need to be done to figure out which patients are most likely to benefit and to sort out the mechanisms of resistance in those who did not benefit.
explored, as well as the identification of new targets and agents that might effectively engage and disrupt these targets. The great majority of melanomas harbor driving oncogenic mutations in either BRAF or NRAS, which leads to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway [15 ]. Targeting this pathway, particularly in patients with BRAF mutant melanoma, has led to major advances in the management of these patients, and has led to the approval of two BRAF inhibitors (dabrafenib and vemurafenib), two MEK inhibitors (trametinib and cobimetinib), and two BRAF/MEK inhibitor combinations (dabrafenib plus trametinib and vemurafenib plus cobimetinib) [4–6,8–10,12] (reviewed in [16]). As BRAF mutations only are seen in half of patients with melanoma, one of the unmet needs in our field is the development of effective, targeted therapy for patients without BRAF mutations. The focus of this review is just that, the description of the molecular underpinnings of BRAF wild-type melanoma and the strategies that have been taken, both preclinically and clinically, to target these. &&
LESSONS FROM THE CANCER GENOME ATLAS The Cancer Genome Atlas (TCGA) project is a remarkably comprehensive and informative endeavor that has aimed to molecularly characterize human cancer. The recent publication of the data in cutaneous melanoma has been a revelation. Although this dataset confirmed the presence of hotspot BRAF (50%) and NRAS (27%) mutations, two other molecular subsets were defined: NF1 subtype, which is mutated in 14% of cases, and the ‘triple wild type’ subtype, which is highlighted by a 186
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lack of BRAF, NRAS, and NF1 mutation [15 ]. As Fig. 1 depicts, the three genetically defined subclasses are predicted to activate the MAPK pathway, as too are various mutations that are identified in the triple wild-type subset, including mutations or amplifications of CKIT, PDGFRa amplification, KDR (VEGFR2) amplification, as well as mutations in the small g-protein a subunits GNAQ and GNA11. Moving beyond MAPK activating mutations, a number of other genomic aberrations are described. The most common is inactivating mutations/loss of CDKN2A, a key genetic regulator of cyclin-dependent kinase 4 (CDK4), cyclin D1 (CCND1), and the cell cycle (reviewed in [17]). CDK4 and CCND1, in turn, are critical regulators of retinoblastoma protein 1, which is a well known tumor suppressor gene that inhibits E2F, the final arbiter of cell cycle activation. Interestingly, CDKN2A is mutated, deleted, or hypomethylated across the four major molecular categories in 40–70% of cases. Additionally, CDK4 and CCND1 mutation or amplification is seen in a substantial minority of patients. And finally, retinoblastoma protein 1 is mutated/deleted in 10% of patients, particular those in the NF1 subset. The widespread nature of these genomic abnormalities suggests that cell cycle dysregulation is not only critical to melanoma development but also may serve as an important target for small molecule inhibition. Other abnormalities have been seen and include those in the phosphatidylinositol 3 kinase (PI3K)/ AKT pathway (including mutation/deletion of PTEN, AKT3 mutations/overexpression, and PIK3CA mutations) and DNA damage response and apoptosis pathways (TP53 mutations in 10–30%, depending on subset, MDM2 and MDM4 amplifications, and abnormalities of key inhibitors of apoptosis such as BCL2, BCL2L12, and MCL1). Additionally, mutations have also been shown to occur in genes related in epigenetic regulation in up to 30% of cases. These include ARID2, ARID1A, ARID1B, IDH1, and EZH2. Another important component of the TCGA was generated with RNA sequencing. The two major findings of this analysis were as follows: fusion events were regularly seen and might drive tumorigenesis and represent targets of small molecule inhibitors; gene expression profiling identified three subclasses, in which all tumors fell, called ‘immune’, ‘keratin’, and ‘MITF low’. Although specific information about how to therapeutically approach using targeted therapy based on this classification is not known, other than the strong hypothesis that immunotherapy may be a good choice for the ‘immune’-rich gene expression profile. Volume 28 Number 2 March 2016
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PDGFR2 CKIT
KDR VEGFR2
NRASGDP
GNAQ/11 NRASGTP
NF1
NRAS-mt RAF
HIPPO pathway
BRAF*
BRAFV600
Immune evasion MEK Cell survival
Invasion and metastasis
Cell cycle progression
ERK
FIGURE 1. Relevant signaling cascades in melanoma. Multiple mediators (in black) and regulators of the mitogen-activated protein pathways have been linked to melanoma. Key oncogenic driver mutations (light gray) include BRAFV600, NRAS (typically at either Q61, G12, or G13), GNAQ and GNA11 (typically in uveal melanoma), and less frequently CKIT, PDGFR2, and KDR/VEGFR2. The tumor suppressor gene NF1 (dark gray) regulates RAS activation.
IMPORTANCE OF THE MITOGENACTIVATED PROTEIN PATHWAY IN MELANOMA Independent of driving mutation status (e.g., BRAF, NRAS, and NF1), the MAPK pathway is nearly always activated in melanoma [18]. Further, the driving oncogenes in melanoma all signal through the pathway via constitutive activation of its key mediators. Canonical signaling pathway starts with cell surface receptor, either g-protein coupled receptor or receptor tyrosine kinase, engagement with ligand. With the activation of g-protein coupled receptor or receptor tyrosine kinase, RAS is activated by guanine nucleotide exchange factor-mediated conversion of RAS bound to guanosine diphosphate to RAS GTP (in either H, K, or N-isoforms) [19]. Of note, NF1 serves as a key regulator of RAS through GTPase-activating protein, which converts the active GTP-bound RAS to GDP-bound RAS [20]. Once in its active form, RAS is capable of interacting with a number of cell signaling mediators, but one of its most critical capabilities is to bind to the RASbinding domain on any of the RAF (A, B, or C) isoforms [21–24]. RAS binding triggers homo and heterodimerization and activation of RAF, a serine threonine kinase that then activates MEK via a phosphorylation event [21,23–26]. Once
activated, MEK1 mediates activation of ERK, which then leads to a number of downstream events including cell cycle activation (through CCND activation), and inhibition of apoptosis (through inhibition of proapoptotic BAD and BIM) [18]. A number of inhibitors of the MAPK pathway mediators have been or are currently under development including four drugs, the BRAF inhibitors vemurafenib and dabrafenib and MEK inhibitors trametinib and cobimetinib, that have been approved by the US Food and Drug Administration for the treatment of BRAF mutant-advanced melanoma, either as single agents (vemurafenib, dabrafenib, and trametinib) or in combination (dabrafenib plus trametinib and vemurafenib plus cobimetinib) [4–6,8–10,12]. Additionally, other RAF inhibitors, including sorafenib, encorafenib, XL281, and R05126766, MEK inhibitors, including selumetinib and binimetinib, and more recently an ERK inhibitor, ulixertinib, have been tested in various unselected and selected cohorts of melanoma patients [27–30,31 ,32–43]. Additional pan-BRAF, MEK, and ERK inhibitors are also under development and are likely to be tested in cohorts of patients with melanoma. What follows is a summary of the recent and current strategies to target the MAPK pathway in melanoma patients without BRAFV600 mutations.
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TARGETED THERAPY IN MITOGENACTIVATED PROTEIN-DRIVEN, MOLECULAR SUBSETS OF MELANOMA Targeting uveal melanoma Mutations in GNAQ and GNA11 are present in the great majority of uveal melanoma and predict signaling through the HIPPO pathway [44–47]. Further, upregulation of a number of signaling pathways including protein kinase C (PKC), MAPK, and PI3K pathways has been described, and preclinical evidence supports the use of inhibitors of MET, MEK, PKC, and PI3K/AKT/mTOR inhibitors, either as a single agent or in combination [48–52,53 ,54–56]. Clinically, single agent MEK inhibition has been an active area of investigation. For example, a randomized phase II trial of selumetinib vs. chemotherapy (either dacarbazine or temozolomide) in 120 patients with metastatic uveal melanoma showed that selumetinib was associated with an improved response rate (14 vs. 0%) and progression-free survival (15.9 vs. 7 weeks, hazard ratio 0.46, P < 0.001) compared with chemotherapy, but no statistically significant improvement in overall survival (11.8 vs. 9.1 months, hazard ratio 0.66, P ¼ 0.09) [31 ]. Disappointingly, a randomized phase III trial of selumetinib plus dacarbazine vs. dacarbazine plus placebo failed to show an improvement in progression-free survival or even an increase in responses in the experimental arm (Carvahal SMR 2015). Other MEK inhibitors have been tested, although not as extensively as selumetinib. For example, a randomized phase II trial of the MEK inhibitor trametinib and the AKT inhibitor GSK2141795 (NCT01979523) is currently enrolling. In addition, tumor reduction has been seen in uveal melanoma patients in the phase I trial of the pan-RAF inhibitor XL281 and in a phase I trial of trametinib plus the CDK4 inhibitor palbociclib [33,57]. Targeting PKC signaling with the PKC inhibitor AEB071, either as a single agent (NCT01430416) or in combination with a MEK inhibitor (NCT01801358) or PI3K inhibitor (NCT02273219), is another strategy being testing in the clinic. The single agent study showed rare responses in this patient population and has not been moved forward. The combination of AEB071 plus binimetinib was tested in a phase Ib trial and has been associated with significant toxicity limiting therapeutic exposure of both AEB071 and binimetinib. Other ongoing studies in this patient population include a number of MET inhibitor trials, including the randomized phase II trial in the Alliance intergroup comparing the MET inhibitor cabozantinib with chemotherapy (NCT01835145). This trial is based &
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on a phase II trial of cabozantinib in patients with melanoma that enrolled 15 patients with metastatic uveal melanoma, 10 of whom had a best response of stable disease and four of these patients were maintained progression free for over 6 months.
Targeting NRAS and NF1 mutant melanoma Activating mutations of NRAS are the second most common oncogenic mutations in melanoma and are present in 20–30% of patients associated with MAPK activation [15 ,58,59]. Mutations in NF1 are seen in a significant minority of patients and represent a third molecularly defined subgroup in melanoma, along with BRAF and NRAS mutant subsets [15 ,60,61 ]. These mutations are associated with inactivation of NF1, which leads to preferential RAS confirmation into GTP-bound, active RAS [60]. Interestingly, NF1 mutation does not always lead to RAS activation, as there is a wide range of the degree of RAS activation with NF1 loss. However, NF1-mutated melanomas are often comutated with so-called ‘RAS-opathy’ genes (which include RASA2, PTPN11, SOS1, RAF1, and SPRED1) that do predict increased RAS activation [61 ,62]. As the major ramification of either NRAS or NF1 mutation is the increased MAPK pathway signaling, targeting mediators of this pathway is logical and supported by preclinical evidence. In fact, pan-RAF inhibitors, MEK inhibitors, and ERK inhibitors all have substantial preclinical activity in NRAS mutant tumors [63–66]. Although there is more variability about how robustly NF1 mutations mediate MAPK activation, these tumors generally are vulnerable to MEK and ERK inhibition in vitro and in vivo [60,61 ]. In patients, the MEK inhibitor binimetinib is associated with a 20% response rate and 4.8-month progression-free survival in NRAS mutant patients [28]. Based on these data, a randomized phase III trial comparing binimetinib with dacarbazine is underway (NCT01763164), and if positive, would change the standard of care for this patient population. There is also a randomized phase II trial of the MEK inhibitor pimasertib compared with dacarbazine that has completed enrollment (NCT01693068). Responses also have been seen in NRAS mutant melanoma patients in the phase I trial of the RAF–MEK inhibitor R0512676, the pan-RAF inhibitor XL281, and in the phase I trial of the ERK inhibitor, ulixertinib. These agents, as well as the pan-RAF inhibitors LY3009120 and MLN2480, and the ERK inhibitor GDC-0994 would also be predicted to have clinical activity and actively are being studied in this patient population. To date, there &&
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have been no reports of activity or inactivity with any of these agents in NF1 mutant patients. Despite promising early clinical data, the majority of NRAS mutant melanoma patients either will not or will only transiently benefit from MEK inhibitors [28]. Thus, strategies to overcome either intrinsic or acquired resistance to MEK inhibitors are needed. In an elegant experiment, investigators (Kwong and colleagues) performed comparative analysis from NRAS mutant melanoma tumors treated with vehicle, MEK inhibitor, and NRAS extinction, determining that CDK4 was the top pathway regulator in the MEK treated but not NRAS extinction model [67]. The consequences of these findings are that CDK4 expression was predicted to mediate MEK inhibitor resistance in NRAS mutant melanoma. Next, the combination of MEK and CDK4/6 inhibitor therapy was compared with either agent alone and shown to be more effective in multiple NRAS xenograft models [67]. Building on this work, a phase I/II trial of the MEK inhibitor binimetinib in combination with the CDK4/6 inhibitor LEE011 in patients with metastatic NRAS mutant melanoma opened to enrollment and the preliminary data were presented at ASCO 2014 and updated at ECCO 2015 [68,69]. Tumor regression initially was seen in most patients across all dose cohorts, and responses were seen in seven of the 22 patients enrolled and another 11 had stable disease, though the response rate seems to be higher than originally described, 41% in the 22 patients enrolled at the 28-day schedule [69]. The results from a similar trial, one evaluating the combination of trametinib plus palbociclib for patients with all solid tumors, was recently reported [57] (NCT02065063). In this dose escalation study, only two responses were seen (one in an NRAS mutant colon cancer patient and the other in a NRAS/BRAF/NF1 wild-type melanoma patient) among the 26 patients treated. In the eight NRAS mutant patients, one responded (the aforementioned colon cancer patient), four had stable disease, and three had progression of disease as a best response. Two NF1 mutant patients were enrolled and both had transient stable disease.
Targeting non-BRAFV600, BRAF mutant melanoma Although the majority of BRAF mutations involve a substitution of valine for a glutamic acid at the 600 position, a number of other, non-V600 mutations have been described. Some, such as K601E and L597Q, lead to a constitutively active kinase and
are susceptible to MEK inhibition [70,71]. Others, including a wide range of mutations at various sites in the kinase domain, lead to a kinase dead state that facilitates heterodimerization with wild-type RAF species (A, B, or C) and activation of the pathway [72]. As preclinical and limited clinical evidence supports the use of MAPK inhibitors in this patient population, clinical trials are exploring the effectiveness of these strategies. In particular, a phase II trial of trametinib (NCT02296112) is specifically enrolling non-V600, BRAF mutant melanoma patients, and a number of phase I trials are targeting these patients in expansion cohorts (NCT01781429 and NCT02014116).
CONCLUSION Recently, large-scale genomic characterization efforts have identified four major subgroups of patients based on the dominant, MAPK-activating, tumor-promoting mutation: BRAF; NRAS; NF1; and triple wild type. With an expanding understanding of the genetic drivers of melanoma, effective therapies have been and will continue to be developed to treat a number of specific, molecularly defined subsets of patients. The most celebrated efforts to date have occurred in the BRAFV600 mutant subset, with four drugs and two drug combinations receiving regulatory approval in the past 4 years. Although this level of success has not been reached to date in other subsets, there is clear rationale for MAPK inhibitors in NRAS, NF1, non-V600 BRAF, and uveal melanoma that will be explored further. The most important efforts will be made in well designed preclinical studies that shed light into the mechanisms of both intrinsic and acquired resistance of single-agent therapy and identify promising combinations to be brought forward into the clinic. Additionally, it will be critical to perform serial biopsies in patients treated with single-agent MEK, pan-RAF, and ERK inhibitors to identify the pharmacodynamic effects of these agents on tumors and ideally to sort out the molecular determinants that predict which patients will benefit and to confirm mechanisms of resistance. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest R.J.S. has served as a consultant for Novartis Pharmaceuticals.
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27. Adjei AA, Cohen RB, Franklin W, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol 2008; 26:2139–2146. 28. Ascierto PA, Schadendorf D, Berking C, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a nonrandomised, open-label phase 2 study. Lancet Oncol 2013; 14:249– 256. 29. Banerji U, Camidge DR, Verheul HM, et al. The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res 2010; 16:1613– 1623. 30. Boasberg PD, Redfern CH, Daniels GA, et al. Pilot study of PD-0325901 in previously treated patients with advanced melanoma, breast cancer, and colon cancer. Cancer Chemother Pharmacol 2011; 68:547–552. 31. Carvajal RD, Sosman JA, Quevedo JF, et al. Effect of selumetinib vs che& motherapy on progression-free survival in uveal melanoma: a randomized clinical trial. JAMA 2014; 311:2397–2405. Results of randomized trial of the MEK inhibitor selumetinib compared with chemotherapy in metastatic uveal melanoma. This trial showed that selumetinib treatment was associated with an improvement in response rate and PFS compared with chemotherapy. 32. Delord J, Houede N, Awada A, et al., eds. First-in-human phase I safety, pharmacokinetic (PK), and pharmacodynamic (PD) analysis of the oral MEKinhibitor AS703026 (two regimens [R]) in patients (pts) with advanced solid tumors. ASCO; 2010; Chicago: J Clin Oncol. 33. Dickson MA, Gordon MS, Edelman G, et al. Phase I study of XL281 (BMS908662), a potent oral RAF kinase inhibitor, in patients with advanced solid tumors. Invest New Drugs 2015; 33:349–356. 34. Dummer R, Robert C, Nyakas M, et al., eds. Initial results from a phase I, openlabel, dose escalation study of the oral BRAF inhibitor LGX818 in patients with BRAF V600 mutant advanced or metastatic melanoma. ASCO; 2013; Chicago, IL: J Clin Oncol. 35. Flaherty KT, Lee SJ, Zhao F, et al. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol 2013; 31:373–379. 36. Hauschild A, Agarwala SS, Trefzer U, et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol 2009; 27:2823– 2830. 37. Lorusso PM, Adjei AA, Varterasian M, et al. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol 2005; 23:5281–5293. 38. LoRusso PM, Krishnamurthi SS, Rinehart JJ, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD0325901 in patients with advanced cancers. Clin Cancer Res 2010; 16:1924–1937. 39. Martinez-Garcia M, Banerji U, Albanell J, et al. First-in-human, phase I doseescalation study of the safety, pharmacokinetics, and pharmacodynamics of RO5126766, a first-in-class dual MEK/RAF inhibitor in patients with solid tumors. Clin Cancer Res 2012; 18:4806–4819. 40. Sharfman WH, Hodi FS, Lawrence DP, et al., eds. Results from the first-inhuman (FIH) phase I study of the oral RAF inhibitor RAF265 administered daily to patients with advanced cutaneous melanoma. ASCO; 2011; Chicago, IL: J Clin Oncol. 41. Sullivan RJ, Weber J, Patel SP, et al., eds. A phase 1b/2 study of BRAF inhibitor (BRAFi) encorafenib (ENCO) plus MEK inhibitor (MEKi) binimetinib (BINI) in cutaneous melanoma patients naive to BRAFi treatment. ASCO; 2015; Chicago, IL. 42. Infante JR, Janku F, Tolcher AW, et al., eds. Dose escalation stage of a first-inclass phase I study of the novel oral ERK 1/2 kinase inhibitor BVD-523 (ulixertinib) in patients with advanced solid tumors. ASCO Annual Meeting; 2015; Chicago, IL: J Clin Oncol. 43. Luken MJ, Roda D, Lopez RP, et al., eds. A pharmacokinetic (PK) and pharmacodynamic (PD) biomarker-driven phase I study of intermittent, low dose intensity schedules of the dual MEK/RAF inhibitor, RO5126766 (RO) in patients (pts) with advanced solid tumors. ASCO Annual Meeting; 2015; Chicago, IL: J Clin Oncol. 44. Van Raamsdonk CD, Bezrookove V, Green G, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 2009; 457:599–602. 45. Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med 2010; 363:2191–2199. 46. Field MG, Harbour JW. GNAQ/11 mutations in uveal melanoma: is YAP the key to targeted therapy? Cancer Cell 2014; 25:714–715. 47. Feng X, Degese MS, Iglesias-Bartolome R, et al. Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry. Cancer Cell 2014; 25:831–845. 48. Ambrosini G, Musi E, Ho AL, et al. Inhibition of mutant GNAQ signaling in uveal melanoma induces AMPK-dependent autophagic cell death. Mol Cancer Ther 2013; 12:768–776.
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Role of mitogen-activated protein targeting in melanoma Sullivan 49. Ambrosini G, Pratilas CA, Qin LX, et al. Identification of unique MEKdependent genes in GNAQ mutant uveal melanoma involved in cell growth, tumor cell invasion, and MEK resistance. Clin Cancer Res 2012; 18:3552– 3561. 50. Ho AL, Musi E, Ambrosini G, et al. Impact of combined mTOR and MEK inhibition in uveal melanoma is driven by tumor genotype. PloS One 2012; 7:e40439. 51. Musi E, Ambrosini G, de Stanchina E, Schwartz GK. The phosphoinositide 3-kinase alpha selective inhibitor BYL719 enhances the effect of the protein kinase C inhibitor AEB071 in GNAQ/GNA11-mutant uveal melanoma cells. Mol Cancer Ther 2014; 13:1044–1053. 52. Surriga O, Rajasekhar VK, Ambrosini G, et al. Crizotinib, a c-Met inhibitor, prevents metastasis in a metastatic uveal melanoma model. Mol Cancer Ther 2013; 12:2817–2826. 53. Chen X, Wu Q, Tan L, et al. Combined PKC and MEK inhibition in uveal & melanoma with GNAQ and GNA11 mutations. Oncogene 2014; 33:4724– 4734. Excellent article describing the preclinical rationale for an important, MEK inhibitorbased trial in uveal melanoma. 54. Sagoo MS, Harbour JW, Stebbing J, Bowcock AM. Combined PKC and MEK inhibition for treating metastatic uveal melanoma. Oncogene 2014; 33:4722–4723. 55. Chattopadhyay C, Grimm EA, Woodman SE. Simultaneous inhibition of the HGF/MET and Erk1/2 pathways affect uveal melanoma cell growth and migration. PLoS One 2014; 9:e83957. 56. von Euw E, Atefi M, Attar N, et al. Antitumor effects of the investigational selective MEK inhibitor TAK733 against cutaneous and uveal melanoma cell lines. Mol Cancer 2012; 11:22. 57. Phase 1b dose-escalation study of trametinib (MEKi) plus palbociclib (CDK4/6i) in patients with advanced solid tumors. Sullivan RJ, Amaria RN, Lawrence DP, et al., editors. Molecular Targets and Cancer Therapeutics. Boston, Massachusetts; 2015. 58. Hodis E, Watson IR, Kryukov GV, et al. A landscape of driver mutations in melanoma. Cell 2012; 150:251–263. 59. Omholt K, Platz A, Kanter L, et al. NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res 2003; 9:6483–6488. 60. Nissan MH, Pratilas CA, Jones AM, et al. Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence. Cancer Res 2014; 74:2340–2350.
61. Krauthammer M, Kong Y, Bacchiocchi A, et al. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nat Genet 2015; 47:996–1002. Wonderful, elegant study describing the role of NF1 alone or in cooperation with other ‘RASopathy genes’ in melanoma. This study also provides an analysis of both the Yale genomic efforts together, which at 213 patients analyzed represents the second largest data set behind the TCGA. 62. Arafeh R, Qutob N, Emmanuel R, et al. Recurrent inactivating RASA2 mutations in melanoma. Nat Genet 2015; 47:1408–1410. 63. Nakamura A, Arita T, Tsuchiya S, et al. Antitumor activity of the selective panRAF inhibitor TAK-632 in BRAF inhibitor-resistant melanoma. Cancer Res 2013; 73:7043–7055. 64. Okaniwa M, Hirose M, Arita T, et al. Discovery of a selective kinase inhibitor (TAK-632) targeting pan-RAF inhibition: design, synthesis, and biological evaluation of C-7-substituted 1,3-benzothiazole derivatives. J Med Chem 2013; 56:6478–6494. 65. Rebecca VW, Alicea GM, Paraiso KH, et al. Vertical inhibition of the MAPK pathway enhances therapeutic responses in NRAS-mutant melanoma. Pigment Cell Melanoma Res 2014; 27:1154–1158. 66. Wong DJ, Robert L, Atefi MS, et al. Antitumor activity of the ERK inhibitor SCH722984 against BRAF mutant, NRAS mutant and wild-type melanoma. Mol Cancer 2014; 13:194. 67. Kwong LN, Costello JC, Liu H, et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med 2012; 18:1503– 1510. 68. Sosman JA, Kittaneh M, Lolkema MPJK, et al., eds. A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRASmutant melanoma: Early encouraging clinical activity. ASCO Annual Meeting; 2014; Chicago, IL: J Clin Oncol. 69. Van Herpen C, Postow MA, Carlino MS, et al., eds. A phase 1b/2 study of ribociclib (LEE011; CDK4/6 inhibitor) in combination with binimetinib (MEK162; MEK inhibitor) in patients with NRAS-mutant melanoma. European Cancer Congress; 2015; Vienna, Austria. 70. Bowyer SE, Rao AD, Lyle M, et al. Activity of trametinib in K601E and L597Q BRAF mutation-positive metastatic melanoma. Melanoma Res 2014; 24:504– 508. 71. Dahlman KB, Xia J, Hutchinson K, et al. BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitors. Cancer Discov 2012; 2:791–797. 72. Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 2010; 140:209–221.
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