Non-BRAF targeted therapies for melanoma: Protein kinase inhibitors in Phase II clinical trials

Expert Opinion on Investigational Drugs

Volumn 23, Issue 4, 2014, Pages 489-500

  Bhatia, Shilpa ^b   Emdad, Luni ^a,b,c   Das, Swadesh K ^b,c   Hamed, Hossein ^b   Dent, Paul ^a,b,c   Sarkar, Devanand ^a,b,c   Fisher, Paul B ^a,b,c  

^a VIRGINIA COMMONWEALTH UNIVERSITY   (United States)

^b VIRGINIA COMMONWEALTH UNIVERSITY   (United States)

^c VIRGINIA COMMONWEALTH UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Clinical trials; Melanoma; Non BRAF mutations; Protein kinase inhibitors; Targeted therapies

Indexed keywords

B RAF KINASE; CYCLIN D1; CYCLIN DEPENDENT KINASE 4; CYCLIN DEPENDENT KINASE INHIBITOR; EPIDERMAL GROWTH FACTOR RECEPTOR 4; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; GNA11 PROTEIN; GNAQ PROTEIN; GUANINE NUCLEOTIDE BINDING PROTEIN; KIT INHIBITOR; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE KINASE INHIBITOR; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN FARNESYLTRANSFERASE INHIBITOR; PROTEIN KINASE B INHIBITOR; PROTEIN KINASE INHIBITOR; PROTEIN TYROSINE KINASE; RAS PATHWAY INHIBITOR; UNCLASSIFIED DRUG; VASCULOTROPIN INHIBITOR; VASCULOTROPIN RECEPTOR INHIBITOR;

ANTIANGIOGENIC THERAPY; CANCER COMBINATION CHEMOTHERAPY; CANCER SURVIVAL; DRUG BINDING; DRUG PROTEIN BINDING; GENE MUTATION; HUMAN; MELANOCYTE; MELANOMA; MOLECULARLY TARGETED THERAPY; PHASE 2 CLINICAL TRIAL (TOPIC); REVIEW; SIGNAL TRANSDUCTION; TREATMENT RESPONSE;

CLINICAL TRIALS, PHASE II AS TOPIC; HUMANS; MELANOMA; MUTATION; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS B-RAF; SKIN NEOPLASMS;

EID: 84896115544     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.2014.884558     Document Type: Review

References (79)

1. Berwick M, Erdei E, Hay J. Melanoma epidemiology and public health. Dermatol Clin 2009;27(2):205-14; viii
2. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999;17(7):2105-16
3. Bedikian AY, Millward M, Pehamberger H, et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol 2006;24(29):4738-45 (Pubitemid 46630937)
4. Carbone PP, Costello W. Eastern Cooperative Oncology Group studies with DTIC (NSC-45388). Cancer Treat Rep 1976;60(2):193-8
5. Weber JS, Dummer R, de Pril V, et al. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase III trial in patients with advanced melanoma. Cancer 2013;119(9):1675-82
6. Erickson CA, Reedy MV. Neural crest development: the interplay between morphogenesis and cell differentiation. Curr Top Dev Biol 1998;40:177-209
7. Dupin E, Glavieux C, Vaigot P, Le Douarin NM. Endothelin 3 induces the reversion of melanocytes to glia through a neural crest-derived glial-melanocytic progenitor. Proc Natl Acad Sci USA 2000;97(14):7882-7 (Pubitemid 30460742)
8. Solus JF, Kraft S. Ras, Raf, and MAP kinase in melanoma. Adv Anat Pathol 2013;20(4):217-26
9. Miller AJ, Mihm MC Jr. Melanoma. N Engl J Med 2006;355(1):51-65
10. Rajagopalan H, Bardelli A, Lengauer C, et al. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 2002;418(6901):934 (Pubitemid 34976022)
11. Quinlan MP, Settleman J. Isoform-specific Ras functions in development and cancer. Future Oncol 2009;5(1):105-16
12. Tsao H, Goel V, Wu H, et al. Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J Invest Dermatol 2004;122(2):337-41 (Pubitemid 38281053)
13. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417(6892):949-54 (Pubitemid 34716871)
14. Perez-Lorenzo R, Zheng B. Targeted inhibition of BRAF kinase: opportunities and challenges for therapeutics in melanoma. Biosci Rep 2012;32(1):25-33
15. Fedorenko IV, Paraiso KH, Smalley KS. Acquired and intrinsic BRAF inhibitor resistance in BRAF V600E mutant melanoma. Biochem Pharmacol 2011;82(3):201-9
16. Paraiso KH, Xiang Y, Rebecca VW, et al. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res 2011;71(7):2750-60
17. Xing F, Persaud Y, Pratilas CA, et al. Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring (V600E)BRAF. Oncogene 2012;31(4):446-57
18. Smalley KS, Lioni M, Dalla Palma M, et al. Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Mol Cancer Ther 2008;7(9):2876-83
19. Van Allen EM, Wagle N, Sucker A, et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov 2013;4(1):94-109
20. Shi H, Hugo W, Kong X, et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov 2013;4(1):80-93 .
21. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006;7(8):606-19 (Pubitemid 44100518)
22. Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 1998;273(22):13375-8 (Pubitemid 28268370)
23. Tsao H, Mihm MC Jr, Sheehan C. PTEN expression in normal skin, acquired melanocytic nevi, and cutaneous melanoma. J Am Acad Dermatol 2003;49(5):865-72 (Pubitemid 37314875)
24. Omholt K, Krockel D, Ringborg U, Hansson J. Mutations of PIK3CA are rare in cutaneous melanoma. Melanoma Res 2006;16(2):197-200 (Pubitemid 44090052)
25. Stahl JM, Sharma A, Cheung M, et al. Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res 2004;64(19):7002-10 (Pubitemid 39331010)
26. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006;24(26):4340-6 (Pubitemid 46630793)
27. Prickett TD, Agrawal NS, Wei X, et al. Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nat Genet 2009;41(10):1127-32
28. Kimple AJ, Bosch DE, Giguere PM, Siderovski DP. Regulators of G-protein signaling and their Galpha substrates: promises and challenges in their use as drug discovery targets. Pharmacol Rev 2011;63(3):728-49
29. Khalili JS, Yu X, Wang J, et al. Combination small molecule MEK and PI3K inhibition enhances uveal melanoma cell death in a mutant GNAQ- and GNA11-dependent manner. Clin Cancer Res 2012;18(16):4345-55
30. Weber A, Hengge UR, Urbanik D, et al. Absence of mutations of the BRAF gene and constitutive activation of extracellular-regulated kinase in malignant melanomas of the uvea. Lab Invest 2003;83(12):1771-6 (Pubitemid 38018540)
31. Zuidervaart W, van Nieuwpoort F, Stark M, et al. Activation of the MAPK pathway is a common event in uveal melanomas although it rarely occurs through mutation of BRAF or RAS. Br J Cancer 2005;92(11):2032-8 (Pubitemid 40897426)
32. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144(5):646-74
33. Rofstad EK, Halsor EF. Vascular endothelial growth factor, interleukin 8, platelet-derived endothelial cell growth factor, and basic fibroblast growth factor promote angiogenesis and metastasis in human melanoma xenografts. Cancer Res 2000;60(17):4932-8
34. Perez DG, Suman VJ, Fitch TR, et al. Phase II trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N047A. Cancer 2009;115(1):119-27
35. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005;353(20):2135-47 (Pubitemid 41653105)
36. Goldstein AM, Chan M, Harland M, et al. Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J Med Genet 2007;44(2):99-106
37. Pomerantz J, Schreiber-Agus N, Liegeois NJ, et al. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2?s inhibition of p53. Cell 1998;92(6):713-23 (Pubitemid 28155311)
38. Daniotti M, Oggionni M, Ranzani T, et al. BRAF alterations are associated with complex mutational profiles in malignant melanoma. Oncogene 2004;23(35):5968-77 (Pubitemid 39093541)
39. Padua RA, Barrass N, Currie GA. A novel transforming gene in a human malignant melanoma cell line. Nature 1984;311(5987):671-3 (Pubitemid 14000661)
40. Zhu K, Hamilton AD, Sebti SM. Farnesyltransferase inhibitors as anticancer agents: current status. Curr Opin Investig Drugs 2003;4(12):1428-35 (Pubitemid 38120205)
41. van Golen KL, Bao L, DiVito MM, et al. Reversion of RhoC GTPaseinduced inflammatory breast cancer phenotype by treatment with a farnesyl transferase inhibitor. Mol Cancer Ther 2002;1(8):575-83
42. Gajewski TF, Salama AK, Niedzwiecki D, et al. Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104). J Transl Med 2012;10:246
43. Hocker T, Tsao H. Ultraviolet radiation and melanoma: a systematic review and analysis of reported sequence variants. Hum Mutat 2007;28(6):578-88 (Pubitemid 46744288)
44. Ascierto PA, Schadendorf D, Berking C, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase II study. Lancet Oncol 2013;14(3):249-56
45. Kirkwood JM, Bastholt L, Robert C, et al. Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res 2012;18(2):555-67
46. Carvajal RD, Sosman JA, Quevedo F, et al. Phase II study of selumetinib (sel) versus temozolomide (TMZ) in gnaq/ Gna11 (Gq/11) mutant (mut) uveal melanoma (UM). J Clin Oncol 2013;31(Suppl):abstract CRA9003 .
47. Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA 2011;305(22):2327-34
48. Guo J, Si L, Kong Y, et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 2011;29(21):2904-9
49. Hodi FS, Corless CL, Giobbie-Hurder A, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sundamaged skin. J Clin Oncol 2013;31(26):3182-90
50. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005;7(2):129-41 (Pubitemid 40248339)
51. Schittenhelm MM, Shiraga S, Schroeder A, et al. Dasatinib (BMS- 354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Res 2006;66(1):473-81 (Pubitemid 43166056)
52. Gorski DH, Leal AD, Goydos JS. Differential expression of vascular endothelial growth factor-A isoforms at different stages of melanoma progression. J Am Coll Surg 2003;197(3):408-18 (Pubitemid 38373300)
53. Erhard H, Rietveld FJ, van Altena MC, et al. Transition of horizontal to vertical growth phase melanoma is accompanied by induction of vascular endothelial growth factor expression and angiogenesis. Melanoma Res 1997;7(Suppl 2):S19-26 (Pubitemid 27501622)
54. Fong TA, Shawver LK, Sun L, et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res 1999;59(1):99-106 (Pubitemid 29062964)
55. Stopeck A, Sheldon M, Vahedian M, et al. Results of a Phase I dose-escalating study of the antiangiogenic agent, SU5416, in patients with advanced malignancies. Clin Cancer Res 2002;8(9):2798-805 (Pubitemid 35025722)
56. Peterson AC, Swiger S, Stadler WM, et al. Phase II study of the Flk-1 tyrosine kinase inhibitor SU5416 in advanced melanoma. Clin Cancer Res 2004;10(12 Pt 1):4048-54 (Pubitemid 38812480)
57. Mita MM, Rowinsky EK, Forero L, et al. A phase II, pharmacokinetic, and biologic study of semaxanib and thalidomide in patients with metastatic melanoma. Cancer Chemother Pharmacol 2007;59(2):165-74 (Pubitemid 44885146)
58. Fruehauf J, Lutzky J, McDermott D, et al. Multicenter, phase II study of axitinib, a selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, in patients with metastatic melanoma. Clin Cancer Res 2011;17(23):7462-9 .
59. Glen H, Mason S, Patel H, et al. E7080, a multi-targeted tyrosine kinase inhibitor suppresses tumor cell migration and invasion. BMC Cancer 2011;11:309
60. Boss DS, Glen H, Beijnen JH, et al. A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours. Br J Cancer 2012;106(10):1598-604
61. Grignol VP, Olencki T, Relekar K, et al. A phase II trial of bevacizumab and high-dose interferon alpha 2B in metastatic melanoma. J Immunother 2011;34(6):509-15
62. Israels ED, Israels LG. The cell cycle. Oncologist 2000;5(6):510-13
63. Tang L, Li G, Tron VA, et al. Expression of cell cycle regulators in human cutaneous malignant melanoma. Melanoma Res 1999;9(2):148-54 (Pubitemid 29331523)
64. Burdette-Radoux S, Tozer RG, Lohmann RC, et al. Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma. Invest New Drugs 2004;22(3):315-22 (Pubitemid 39012571)
65. Carlson BA, Dubay MM, Sausville EA, et al. Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res 1996;56(13):2973-8 (Pubitemid 26200251)
66. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369(2):122-33
67. Wang XY, Zuo D, Sarkar D, Fisher PB. Blockade of cytotoxic T-lymphocyte antigen-4 as a new therapeutic approach for advanced melanoma. Expert Opin Pharmacother 2011;12(17):2695-706
68. Friedman EB, Shang S, de Miera EV, et al. Serum microRNAs as biomarkers for recurrence in melanoma. J Transl Med 2012;10:155 .
69. Ng SB, Turner EH, Robertson PD, et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature 2009;461(7261):272-6
70. Turner EH, Lee C, Ng SB, et al. Massively parallel exon capture and library-free resequencing across 16 genomes. Nat Methods 2009;6(5):315-16
71. Pleasance ED, Cheetham RK, Stephens PJ, et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 2010;463(7278):191-6
72. Marti RM, Sorolla A, Yeramian A. New therapeutic targets in melanoma. Actas Dermosifiliogr 2012;103(7):579-90
73. Sullivan RJ, Atkins MB. Molecular targeted therapy for patients with melanoma: the promise of MAPK pathway inhibition and beyond. Expert Opin Investig Drugs 2010;19(10):1205-16
74. Thomas S, Quinn BA, Das SK, et al. Targeting the Bcl-2 family for cancer therapy. Expert Opin Ther Targets 2013;17(1):61-75 . This article describes some of the novel Bcl-2 family inhibitors and BH3 mimetics that could provide clinical benefit.
75. Quinn BA, Dash R, Azab B, et al. Targeting Mcl-1 for the therapy of cancer. Expert Opin Investig Drugs 2011;20(10):1397-411
76. Das SK, Bhutia SK, Azab B, et al. MDA-9/syntenin and IGFBP-2 promote angiogenesis in human melanoma. Cancer Res 2013;73(2):844-54 .
77. Boukerche H, Su ZZ, Prevot C, et al. mda-9/Syntenin promotes metastasis in human melanoma cells by activating c-Src. Proc Natl Acad Sci USA 2008;105(41):15914-19
78. Sarkar D, Boukerche H, Su ZZ, Fisher PB. mda-9/Syntenin: more than just a simple adapter protein when it comes to cancer metastasis. Cancer Res 2008;68(9):3087-93
79. Davies MA, Samuels Y. Analysis of the genome to personalize therapy for melanoma. Oncogene 2010;29(41):5545-55