Drugs

, Volume 78, Issue 5, pp 549–566 | Cite as

BRAF and MEK Inhibitors: Use and Resistance in BRAF-Mutated Cancers

Review Article

Abstract

The mitogen activated protein kinase/extracellular signal-related kinase (MAPK/ERK) signaling pathway serves an integral role in growth, proliferation, differentiation, migration, and survival of all mammalian cells. Aberrant signaling of this pathway is often observed in several types of hematologic and solid malignancies. The most frequent insult to this signaling cascade, leading to its constitutive activation, is to the serine/threonine kinase rapidly accelerating fibrosarcoma (RAF). Considering this, the development and approval of various small-molecule inhibitors targeting the MAPK/ERK pathway has become a mainstay of treatment as either mono- or combination therapy in these cancers. Although effective initially, a major clinical barrier with these inhibitors is the relapse of patients due to drug resistance. Knowledge of the mechanisms of resistance to these drugs is still premature, highlighting the need for a more in-depth understanding of how patients become insensitive to these pharmacologic interventions. Herein, we will succinctly summarize the milestones in the approval of select MAPK/ERK pathway inhibitors, their use in patients, and major modes of resistance.

Notes

Compliance with Ethical Standards

Funding

The authors would like to acknowledge the following sources of funding that supported in part the work and effort completed on the manuscript. These include funding from the Department of Surgery at the University of Michigan (MSC and TW) as well as grant funding from the National Institute of Health (R01CA120458 and R01CA216919—MSC) and (T32GM007767—JNS).

Conflict of interest

MSC has received consulting fees from EEPI and Acousys Biomedical Devices LLC in the last year—unrelated to the current manuscript. He is cofounder of NanoPharm LLC, and MedGuider LLC and currently serves as CEO of MedGuider. He has ownership interest in both companies, but no royalties have been generated from either company and neither company is related at all to the topic in the manuscript. The other authors declare no conflict of interest.

References

  1. 1.
    Zhang W, Liu HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 2002;12:9–18.PubMedGoogle Scholar
  2. 2.
    Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signaling pathways in cancer. Oncogene. 2007;26:3279–90.PubMedGoogle Scholar
  3. 3.
    Robert PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen activated protein kinase cascade for the treatment of cancer. Oncogene. 2007;26:3291–310.Google Scholar
  4. 4.
    Seshacharyulu P, Ponnusamy MP, Haridas D, et al. Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Thargets. 2012;16(1):15–31.Google Scholar
  5. 5.
    Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.Google Scholar
  6. 6.
    Prior IA, Lewis PD, Mattos C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012;72(10):2457–67.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Ascierto PA, Kirkwood JM, Grob JJ, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10:85.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Akbani R, Cancer Genome Atlas Network et al. Genomic classification of cutaneous melanoma. Cell 2015;161:1681–1696.Google Scholar
  9. 9.
    Tang KT, Lee CH. BRAF mutation in papillary thyroid carcinoma: pathogenic role and clinical implications. J Clin Med Assoc. 2010;73(3):113–28.Google Scholar
  10. 10.
    Clarke CN, Kopetz ES. BRAF mutant colorectal cancer as a distinct subset of colorectal cancer: clinical characteristics, clinical behavior, and response to targeted therapies. J Gastrointest Oncol. 2015;6(6):660–7.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Yarchoan M, LiVolsi VA, Brose MS. BRAF mutation and thyroid cancer recurrence. Clin Oncol. 2015;33(1):7–8.Google Scholar
  12. 12.
    Tiacci E, Trifonov V, Schiavoni G, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med. 2011;364:2305–15.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Ragad T. Targeting RTK signaling pathways in cancer. Cancers (Basel). 2015;7(3):1758–84.Google Scholar
  14. 14.
    Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809–19.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Ribas A, Kim KB, Schuchter LM, et al. BRIM-2: an open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAFV600E mutation-positive melanoma. J Clin Oncol. 2011;29(Suppl):8509.Google Scholar
  16. 16.
    Zhang C, Spevak W, et al. RAF inhibitors that evade paradoxical MAPK pathway activation. Nature. 2015;526:583–6.PubMedGoogle Scholar
  17. 17.
    Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366(3):207–15.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Oberholzer PA, et al. RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J Clin Oncol. 2012;30:316–21.PubMedGoogle Scholar
  19. 19.
    Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Tiacci E, Park JH, De Carolis L, et al. Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia. N Engl J Med. 2015;373:1733–47.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140(2):209–21.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Hatzivassilious G, Song K, Yen I, et al. RAF inhibitors prime wild-type RAF to active the MAPK pathway and enhance growth. Nature. 2010;464:431–5.Google Scholar
  23. 23.
    Holderfield M, Merritt H, Chan J, et al. RAF inhibitors active the MAPK pathway by relieving inhibitory autophosphorylation. Cell. 2013;23(5):594–602.Google Scholar
  24. 24.
    Falchoook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumors: a phase 1 dose-escalation trial. Lancet. 2012;379(9829):1893–901.Google Scholar
  25. 25.
    Ascierto PA, Minor D, Ribas A, et al. Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol. 2013;31(26):3205–11.PubMedGoogle Scholar
  26. 26.
    Hauschild A, Grob JJ, Demidov LV, et al. Debrafenib in BRAF-mutated metastatic melanoma: a multicenter, open-label phase 3 randomized controlled trial. Lancet. 2012;380(9839):358–65.PubMedGoogle Scholar
  27. 27.
    Delord JP, Robert C, Nyakas M, et al. Phase I dose-escalation and -expansion study of the BRAF inhibitor encorafenib (LGX818) in metastatic BRAF-mutant melanoma. Clin Can Res. 2017;23(18):5339–48.Google Scholar
  28. 28.
    US FDA hematology/oncology (cancer) approvals and safety notifications. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm. Accessed Sept 2016.
  29. 29.
    Ali SM, He J, Carson W, et al. Extended antitumor response of a BRAF V600E papillary thyroid carcinoma to vemurafenib. Case Rep Oncol. 2014;7(2):343–8.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal cell carcinoma. N Engl J Med. 2007;356:125–34.PubMedGoogle Scholar
  31. 31.
    Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.PubMedGoogle Scholar
  32. 32.
    Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomized, double-blind, phase 3 trial. Lancet. 2014;384(9940):319–28.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Zhang L, Singh RR, Stingo F, et al. BRAAF kinase domain mutation are present in a subset of chronic myelomonocytic leukemia with wild-type RAS. Am J Hematol. 2014;89(5):499–504.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:782–9.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14.PubMedGoogle Scholar
  36. 36.
    Kim KB, Kefford R, Pavlick AC, et al. Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol. 2013;31:482–9.PubMedGoogle Scholar
  37. 37.
    Gencler B, Gonul M. Cutaneous side effects of BRAF inhibitors in advanced melanoma: review of the literature. Dermatol Res Pract. 2016;2016:5361569.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Blumenschein GR Jr, Smit EF, Planchard D, et al. A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)dagger. Ann Oncol. 2015;26:894–901.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Hoeflich KP, Merchant M, Orr C, et al. Intermittent administration of MEK inhibitor GDC-0973 plus PI3 K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Cancer Res. 2012;72(1):210–9.PubMedGoogle Scholar
  40. 40.
    Ribas A, Gonzalez R, Pavlick A, et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. Lancet Oncol. 2014;15(9):954–65.PubMedGoogle Scholar
  41. 41.
    FDA approves Cotellic as part of combination treatment for advanced melanoma. In: fda.gov. 2015. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm471934.htm. Accessed 17 Dec 2017.
  42. 42.
    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;16:1613–23.PubMedGoogle Scholar
  43. 43.
    Chakravarty D, Santos E, Ryder M, et al. Small-molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation. J Clin Invest. 2011;121:4700–11.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Ho AL, Grewal RK, Leboeuf R, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med. 2013;368:623–32.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Hainsworth JD, Cebotaru CL, Kanarev V, et al. A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens. J Thorac Oncol. 2010;5:1630–6.PubMedGoogle Scholar
  46. 46.
    Janne PA, Shaw AT, Pereira JR, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 2013;14:38–47.PubMedGoogle Scholar
  47. 47.
    Janne PA, van den Heuvel MM, Barlesi F, et al. Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: the SELECT-1 randomized clinical trial. JAMA. 2017;317:1844–53.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Awada A, Delord JP, Houede N et al. Safety and recommended phase II dose (RP2D) of the selective oral MEK1/2 inhibitor pimasertib (MSC1936369B/AS703026): results of a phase I trial. Eur J Cancer. 2012;48:6185–6186 (abstract 604).Google Scholar
  49. 49.
    Macarulla T, Cervantes A, Tabernero J, et al. Phase I study of FOLFIRI plus pimasertib as second-line treatment for KRAS-mutated metastatic colorectal cancer. Br J Cancer. 2015;112(12):1874–81.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Lebbe C, Lesimple T, Kruit W, et al. Pimasertib (PIM) versus dacarbazine (DTIC) in patients (pts) with cutaneous NRAS melanoma: a controlled, open-label phase II trial with crossover. Ann Oncol. 2016;27(6):1136.Google Scholar
  51. 51.
    Binimetinib (MEK 162). In: arraybiopharma.com. 2017. http://www.arraybiopharma.com/product-pipeline/binimetinib/. Accessed 17 Dec 2017.
  52. 52.
    Lee PA, Wallace E, Marlow A et al. Preclinical development of ARRY-162, a potent and selective MEK 1/2 inhibitor. Cancer Res. 2010;70:2515 (abstract).Google Scholar
  53. 53.
    Bendell JC, Javle M, Bekaii-Sabb TS, et al. A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor. Br J Cancer. 2017;116(5):575–83.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Cho M, Gong J, Frankel P, et al. A phase I clinical trial of binimetinib in combination with FOLFOX in patients with advanced metastatic colorectal cancer who failed prior standard therapy. Oncotarget. 2017;8(45):79750–60.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Rizos H, Menzies AM, Pupo GM, et al. BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin Cancer Res. 2014;20:1965–77.PubMedGoogle Scholar
  56. 56.
    Van Allen EM, Wagle N, Sucker A, et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014;4:94–109.PubMedGoogle Scholar
  57. 57.
    Shi H, Hugo W, Kong X, et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014;4:80–93.PubMedGoogle Scholar
  58. 58.
    Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464:427–30.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition verus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371:1877–88.PubMedGoogle Scholar
  60. 60.
    Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867–76.PubMedGoogle Scholar
  61. 61.
    Dummer R, Ascierto PA, Gogas HJ, et al. Results of COLUMBUS Part 1: A phase 3 trial of encorafenib (enco) plus binimetinib (bini) versus vemurafenib (vem) or enco in BRAF-mutant melanoma. Array BioPharma Inc. Society for Melanoma Research 2016 Congress. Nov 2011. Boston, MA.Google Scholar
  62. 62.
    Dummer R, Ascierto PA, Gogas HJ, et al. Results of COLUMBUS Part 2: a phase 3 trial of encorafenib plus binimetinib versus encorafenib in BRAF-mutant melanoma. Array BioPharma Inc. ESMO Congress. 2017. Madrid, Spain.Google Scholar
  63. 63.
    Luke JJ, Flaherty KT, Ribas A, Long GV. Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Onc. 2017;14:463–82.Google Scholar
  64. 64.
    Ribas A, Hodi FS, Callahan M, et al. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368(14):1365–6.PubMedGoogle Scholar
  65. 65.
    Ribas A, Hodi FS, Lawrence D, et al. KEYNOTE-022 update: phase 1 study of first of first -line pembrolizumab plus dabrafenib and trametinib for BRAF-mutant advanced melanoma. ESMO Congress. 2017. Abstract 1216O.Google Scholar
  66. 66.
    Cui G, Liu D, Li W, et al. A meta-analysis of the association between BRAF mutation and nonsmall cell lung cancer. Medicine (Baltimore). 2017;96:e6552.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Planchard D, Besse B, Groen HJ, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016;17:984–93.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Barlesi F, Mazieres J, Merlio JP, et al. Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet. 2016;387:1415–26.PubMedGoogle Scholar
  69. 69.
    FDA grants regular approval to dabrafenib and trametinib combination for metastatic NSCLC with BRAF V600E mutation. In: fda.gov. 2017. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm564331.htm. Accessed 17 Dec 2017.
  70. 70.
    Cohen R, Cervera P, Svrcek M, et al. BRAF-mutated colorectal cancer: what is the optimal strategy for treatment? Curr Treat Opt Oncol. 2017;18:9.Google Scholar
  71. 71.
    Yaeger R, Cercek A, O’Reilly EM, et al. Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients. Clin Cancer Res. 2015;21:1313–20.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Geng F, Wang Z, Yin H, et al. Molecular targeted drugs and treatment of colorectal cancer: recent progress and future perspectives. Cancer Biother Radiopharm. 2017;32:149–60.PubMedGoogle Scholar
  73. 73.
    Yang H, Higgins B, Kolinsky K, et al. Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer. Cancer Res. 2012;72:779–89.PubMedGoogle Scholar
  74. 74.
    Hong DS, Morris VK, El Osta B, et al. Phase IB study of vemurafenib in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with BRAFV600E mutation. Cancer Discov. 2016;6:1352–65.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Kopetz S. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406). In: ascopubs.org. http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.3505. 2017. Accessed 24 Jul 2017.
  76. 76.
    Manzano JL, Layos L, Buges C, et al. Resistant mechanisms to BRAF inhibitors in melanoma. Ann Transl Med. 2016;4(12):237.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Solit DB, Rosen N. Resistance to BRAF inhibitors in melanomas. N Engl J Med. 2011;362:772–4.Google Scholar
  78. 78.
    Mao M, Feng T, Mariadason JM, Tsao CC, et al. Resistance to BRAF inhibition in BRAF-mutant colon cancer can ber overcome with PI3 K inhibition or demethylating agents. Clin Cancer Res. 2012;19(3):657–67.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Prahallad A, Sun C, Huang S. Unresponsiveness of colon cancer to BRAF (V600E) inhibition through feedback activation of EGFR. Nature. 2012;483(7387):100–3.PubMedGoogle Scholar
  80. 80.
    Halaban R. RAC1 and melanoma. Clin Ther. 2015;37(3):682–5.PubMedGoogle Scholar
  81. 81.
    Rajendran V, Gopalakrishnan C, Purohit R. Impact of point mutation P29S in RAC1 on tumorigenesis. Tumour Biol. 2016;37(11):15293–304.PubMedGoogle Scholar
  82. 82.
    Zhou Y, Liao Q, Han Y, et al. Rac1 overexpression is correlated with epithelial mesenchymal transition and predicts poor prognosis in non-small lung cancer. J Cancer. 2016;7(14):2100–9.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Liu B, Xiong J, Liu G, et al. High expression of Rac1 is correlated with partial reversed cell polarity and poor prognosis in invasive ductal carcinoma of the breast. Tumor Biol. 2017;39(7):1010428317710908.Google Scholar
  84. 84.
    Watson IR, Li L, Cabeceiras PK, et al. The RAC1 P29S hotspot mutation in melanoma confers resistance to pharmacological inhibition of RAF. Can Res. 2014.  https://doi.org/10.1158/0008-5472.CAN-14-1232-T.Google Scholar
  85. 85.
    Stahl JM, Cheung M, Sharma A, et al. Loss of PTEN promotes tumor development in malignant melanoma. Can Res. 2003;63(11):2881–90.Google Scholar
  86. 86.
    Wu H, Giel V, Haluska FG. PTEN signaling pathways in melanoma. Oncogene. 2003;22:3113–22.PubMedGoogle Scholar
  87. 87.
    Kennedy SG, Wagner AJ, Conzen SD, et al. The PI3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dev. 1997;11:701–13.PubMedGoogle Scholar
  88. 88.
    Cheney IW, Johnson DE, Vaillancourt MT, et al. Suppression of tumorigenicity of glioblastoma cells by adenovirus-mediated MMAC1/PTEN gene transfer. Cancer Res. 1998;58:2331–4.PubMedGoogle Scholar
  89. 89.
    Paraiso KH, Xiang Y, Rebecca VW, et al. PTEN loss confers BRAF inhibitor resistance to melanoma cells through suppression of BIM expression. Can Res. 2011;71(7):2750–60.Google Scholar
  90. 90.
    Gogada R, Yadav N, Liu J, et al. BIM, a proapoptotic protein, upregulated via transcription factor E2F1-deendet mechanism, functions as a prosurvival molecule in cancer. JBC. 2012.  https://doi.org/10.1074/jbc.M112.386102.Google Scholar
  91. 91.
    Catalanotti F, Cheng DT, Shoushtari AN, et al. PTEN loss-of-function alterations are associated with intrinsic resistance to BRAF inhibitors in metastatic melanoma. JCO Precis Oncol. 2017.  https://doi.org/10.1200/PO.1600054.Google Scholar
  92. 92.
    Sheppard KE, McArthur GA. The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma. Clin Cancer Res. 2013.  https://doi.org/10.1158/1078-0432.CCR-13-0259.Google Scholar
  93. 93.
    Smalley KS, Lioni M, Dalla 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.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009;361(1):98–9.PubMedGoogle Scholar
  95. 95.
    Kopetz S, Desai J, Chan E, et al. PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors. J Clin Oncol. 2010;28(10):3534.Google Scholar
  96. 96.
    Kulkarni A, Al-Hraishawi H, Simhadri S, et al. BRAF fusion as a novel mechanism of acquired resistance to vemurafenib in BRAFv600E mutant melanomas. Biol Hum Tumors. 2017.  https://doi.org/10.1158/1078-0432.CCR-16-0758.Google Scholar
  97. 97.
    Kim HS, Jung M, Kang HN, et al. Oncogenic BRAF fusions in mucosal melanomas active the MAPK pathway and are sensitive to MEK/PI3K inhibition or MEK/CDK4/6 inhibition.Google Scholar
  98. 98.
    Emery CM, Vijayendran KG, Zipser MC. MEK1 mutations confer resistance to MEK and BRAF inhibition. PNAS. 2009.  https://doi.org/10.1073/pnas.0905833106.Google Scholar
  99. 99.
    Johannessen CM, Boehm JS, Kim SY. COT/MAP3K8 drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468(7326):968–72.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33(17):1974–82.PubMedPubMedCentralGoogle Scholar
  101. 101.
    O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol. 2016;13:417–30.PubMedGoogle Scholar
  102. 102.
    Goel HL, Mercurio AM. VEGF targets the tumor cell. Nat Rev Cancer. 2013;13:871–82.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to BRAF(V600E) inhibition by RTK or NRAS upregulation. Nature. 2010;468(7326):973–7.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Shi H, Kong X, Ribas A, et al. Combinatorial treatments that overcome PDGFRβ-driven resistance of melanoma cell to BRAF(V600E) inhibition. Cancer Res. 2011;71:5067–74.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Perna D, Karreth FA, Rust AG. BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model. PNAS. 2015.  https://doi.org/10.1073/pnas.1418163112.Google Scholar
  106. 106.
    Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase-AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.PubMedGoogle Scholar
  107. 107.
    Paraiso KHT, 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.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Sweetlove M, Wrightson E, Kolekar S, et al. Inhibitors of pan-PI3 K signaling synergize with BRAF or MEK inhibitors to prevent BRAF-mutant melanoma cell growth. Front Oncol. 2015;5:135.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Temraz S, Mukerji D, Shamseddine A. Dual inhibition of MEK and PI3K pathway in KRAS and BRAF mutated colorectal cancers. Int J Mol Sci. 2015;16(9):22976–88.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Schopf FH, Biebl MM, Buchner J. The HSP90 chaperone machinery. Nat Rev Mol Cell Biol. 2017;18:345–60.PubMedGoogle Scholar
  111. 111.
    Miyata Y, Nakamoto H, Necker L. The therapeutic target Hsp90 and cancer hallmarks. Curr Pharm Des. 2013;19(3):347–65.PubMedGoogle Scholar
  112. 112.
    Pacey S, Gore M, Chao D, et al. A phase II trial of 17-allylamino, 17-demthoxygeldanamycin (17-AAG, tanespimycin) in patients with metastatic melanoma. Invest New Drugs. 2012;30(1):341–9.PubMedGoogle Scholar
  113. 113.
    Byrd KM, Subramanian C, Sanchez J, et al. Synthesis and biological evaluation of Novobiocin core analogues as Hsp90 inhibitors. Chem Eur J. 2016;22:6921–31.PubMedPubMedCentralGoogle Scholar
  114. 114.
    White PT, Subramanian C, Zhu Q, et al. Novel Hsp90 inhibitors effectively target functions of thyroid cancer stem cell preventing migration and invasion. Surgery. 2016;159(1):142–51.PubMedGoogle Scholar
  115. 115.
    Raveendran S, Rao A, and Storkus W. Combination immunotherapy of melanoma by inhibiting HSP90 and targeting its client proteins (TUM7P.934). J Immunol. 2014;192:1 Supplemental 203.16.Google Scholar
  116. 116.
    Chai RC, Vieusseux JL, Lang BJ, et al. Histone deacteylase activity mediates acquired resistance towards structurally diverse hsp90 inhibitors. Mol Oncol. 2017;11(5):567–83.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(11):1087–95.PubMedGoogle Scholar
  118. 118.
    National Comprehensive Cancer Network. Melanoma NCCN Guidelines with NCCN Evidence Blocks. In: nccn.org. https://www.nccn.org/professionals/physician_gls/pdf/melanoma_blocks.pdf. 2017. Accessed 24 Jul 2017.
  119. 119.
    National Comprehensive Cancer Network. Thyroid Carcinoma NCCN Guidelines with NCCN Evidence Blocks. In: nccn.org. https://www.nccn.org/professionals/physician_gls/pdf/thyroid_blocks.pdf. 2017. Accessed 24 Jul 2017.
  120. 120.
    National Comprehensive Cancer Network. Colon Cancer NCCN Guidelines with NCCN Evidence Blocks. In: nccn.org. https://www.nccn.org/professionals/physician_gls/pdf/colon_blocks.pdf. 2017. Accessed 24 Jul 2017.
  121. 121.
    National Comprehensive Cancer Network. Non-Small Cell Lung Cancer NCCN Guidelines with NCCN Evidence Blocks. In: nccn.org. https://www.nccn.org/professionals/physician_gls/pdf/nscl_blocks.pdf. 2017. Accessed 24 Jul 2017.
  122. 122.
    National Comprehensive Cancer Network. Hairy Cell Leukemia NCCN Guidelines with NCCN Evidence Blocks. In: nccn.org. https://www.nccn.org/professionals/physician_gls/pdf/hairy_cell.pdf. 2017. Accessed 24 Jul 2017.
  123. 123.
    Lexicomp. Vemurafenib: Drug Information. In: UpToDate.com. https://www.uptodate.com/contents/vemurafenib-drug-information?source=search_result&search=Vemurafenib&selectedTitle=1~42. 2017. Accessed 24 Jul 2017.
  124. 124.
    Lexicomp. Dabrafenib: Drug Information. In: UpToDate.com. https://www.uptodate.com/contents/dabrafenib-drug-information?source=search_result&search=dabrafenib&selectedTitle=1~33. 2017. Accessed 24 Jul 2017.
  125. 125.
    Lexicomp. Sorafenib: Drug Information. In: UpToDate.com. https://www.uptodate.com/contents/sorafenib-drug-information?source=search_result&search=sorafenib&selectedTitle=1~107. 2017. Accessed 24 Jul 2017.
  126. 126.
    Lexicomp. Trametinib: Drug Information. In: UpToDate.com. https://www.uptodate.com/contents/trametinib-drug-information?source=search_result&search=trametinib&selectedTitle=1~28. 2017. Accessed 24 Jul 2017.
  127. 127.
    Lexicomp. Cobimetinib: Drug Information. In: UpToDate.com. https://www.uptodate.com/contents/cobimetinib-drug-information?source=search_result&search=cobimetinib&selectedTitle=1~18. 2017. Accessed 24 Jul 2017.

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PharmacologyUniversity of Michigan Medical SchoolAnn ArborUSA
  2. 2.Department of SurgeryMichigan MedicineAnn ArborUSA

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