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Erschienen in: Drugs 5/2018

01.04.2018 | Review Article

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

verfasst von: Jaquelyn N. Sanchez, Ton Wang, Mark S. Cohen

Erschienen in: Drugs | Ausgabe 5/2018

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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.
Literatur
1.
Zurück zum Zitat Zhang W, Liu HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 2002;12:9–18.PubMedCrossRef Zhang W, Liu HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 2002;12:9–18.PubMedCrossRef
2.
Zurück zum Zitat Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signaling pathways in cancer. Oncogene. 2007;26:3279–90.PubMedCrossRef Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signaling pathways in cancer. Oncogene. 2007;26:3279–90.PubMedCrossRef
3.
Zurück zum Zitat Robert PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen activated protein kinase cascade for the treatment of cancer. Oncogene. 2007;26:3291–310.CrossRef Robert PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen activated protein kinase cascade for the treatment of cancer. Oncogene. 2007;26:3291–310.CrossRef
4.
Zurück zum Zitat 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.CrossRef 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.CrossRef
5.
Zurück zum Zitat Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.
8.
Zurück zum Zitat Akbani R, Cancer Genome Atlas Network et al. Genomic classification of cutaneous melanoma. Cell 2015;161:1681–1696. Akbani R, Cancer Genome Atlas Network et al. Genomic classification of cutaneous melanoma. Cell 2015;161:1681–1696.
9.
Zurück zum Zitat Tang KT, Lee CH. BRAF mutation in papillary thyroid carcinoma: pathogenic role and clinical implications. J Clin Med Assoc. 2010;73(3):113–28.CrossRef Tang KT, Lee CH. BRAF mutation in papillary thyroid carcinoma: pathogenic role and clinical implications. J Clin Med Assoc. 2010;73(3):113–28.CrossRef
10.
Zurück zum Zitat 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.PubMedPubMedCentral 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.PubMedPubMedCentral
11.
Zurück zum Zitat Yarchoan M, LiVolsi VA, Brose MS. BRAF mutation and thyroid cancer recurrence. Clin Oncol. 2015;33(1):7–8.CrossRef Yarchoan M, LiVolsi VA, Brose MS. BRAF mutation and thyroid cancer recurrence. Clin Oncol. 2015;33(1):7–8.CrossRef
13.
Zurück zum Zitat Ragad T. Targeting RTK signaling pathways in cancer. Cancers (Basel). 2015;7(3):1758–84.CrossRef Ragad T. Targeting RTK signaling pathways in cancer. Cancers (Basel). 2015;7(3):1758–84.CrossRef
14.
15.
Zurück zum Zitat 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.CrossRef 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.CrossRef
16.
Zurück zum Zitat Zhang C, Spevak W, et al. RAF inhibitors that evade paradoxical MAPK pathway activation. Nature. 2015;526:583–6.PubMedCrossRef Zhang C, Spevak W, et al. RAF inhibitors that evade paradoxical MAPK pathway activation. Nature. 2015;526:583–6.PubMedCrossRef
17.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
18.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
19.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
20.
21.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
22.
Zurück zum Zitat 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.CrossRef 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.CrossRef
23.
Zurück zum Zitat Holderfield M, Merritt H, Chan J, et al. RAF inhibitors active the MAPK pathway by relieving inhibitory autophosphorylation. Cell. 2013;23(5):594–602. Holderfield M, Merritt H, Chan J, et al. RAF inhibitors active the MAPK pathway by relieving inhibitory autophosphorylation. Cell. 2013;23(5):594–602.
24.
Zurück zum Zitat 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.CrossRef 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.CrossRef
25.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
26.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
27.
Zurück zum Zitat 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.CrossRef 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.CrossRef
29.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
30.
Zurück zum Zitat Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal cell carcinoma. N Engl J Med. 2007;356:125–34.PubMedCrossRef Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal cell carcinoma. N Engl J Med. 2007;356:125–34.PubMedCrossRef
31.
Zurück zum Zitat Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.PubMedCrossRef Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.PubMedCrossRef
32.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
33.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
34.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
35.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
36.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
37.
Zurück zum Zitat Gencler B, Gonul M. Cutaneous side effects of BRAF inhibitors in advanced melanoma: review of the literature. Dermatol Res Pract. 2016;2016:5361569.PubMedPubMedCentralCrossRef Gencler B, Gonul M. Cutaneous side effects of BRAF inhibitors in advanced melanoma: review of the literature. Dermatol Res Pract. 2016;2016:5361569.PubMedPubMedCentralCrossRef
38.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
39.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
40.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
42.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
43.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
44.
45.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
46.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
47.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
48.
Zurück zum Zitat 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). 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).
49.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
50.
Zurück zum Zitat 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. 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.
52.
Zurück zum Zitat 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). 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).
53.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
54.
Zurück zum Zitat 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.PubMedPubMedCentral 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.PubMedPubMedCentral
55.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
56.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
57.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
58.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
59.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
60.
Zurück zum Zitat Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867–76.PubMedCrossRef Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867–76.PubMedCrossRef
61.
Zurück zum Zitat 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. 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.
62.
Zurück zum Zitat 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. 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.
63.
Zurück zum Zitat Luke JJ, Flaherty KT, Ribas A, Long GV. Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Onc. 2017;14:463–82.CrossRef Luke JJ, Flaherty KT, Ribas A, Long GV. Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Onc. 2017;14:463–82.CrossRef
64.
Zurück zum Zitat Ribas A, Hodi FS, Callahan M, et al. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368(14):1365–6.PubMedCrossRef Ribas A, Hodi FS, Callahan M, et al. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368(14):1365–6.PubMedCrossRef
65.
Zurück zum Zitat 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. 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.
66.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
67.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
68.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
70.
Zurück zum Zitat 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.CrossRef 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.CrossRef
71.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
72.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
73.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
74.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
77.
Zurück zum Zitat Solit DB, Rosen N. Resistance to BRAF inhibitors in melanomas. N Engl J Med. 2011;362:772–4.CrossRef Solit DB, Rosen N. Resistance to BRAF inhibitors in melanomas. N Engl J Med. 2011;362:772–4.CrossRef
78.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
79.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
81.
Zurück zum Zitat Rajendran V, Gopalakrishnan C, Purohit R. Impact of point mutation P29S in RAC1 on tumorigenesis. Tumour Biol. 2016;37(11):15293–304.PubMedCrossRef Rajendran V, Gopalakrishnan C, Purohit R. Impact of point mutation P29S in RAC1 on tumorigenesis. Tumour Biol. 2016;37(11):15293–304.PubMedCrossRef
82.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
83.
Zurück zum Zitat 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. 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.
85.
Zurück zum Zitat Stahl JM, Cheung M, Sharma A, et al. Loss of PTEN promotes tumor development in malignant melanoma. Can Res. 2003;63(11):2881–90. Stahl JM, Cheung M, Sharma A, et al. Loss of PTEN promotes tumor development in malignant melanoma. Can Res. 2003;63(11):2881–90.
86.
87.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
88.
Zurück zum Zitat 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.PubMed 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.PubMed
89.
Zurück zum Zitat 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.CrossRef 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.CrossRef
93.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
94.
Zurück zum Zitat Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009;361(1):98–9.PubMedCrossRef Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009;361(1):98–9.PubMedCrossRef
95.
Zurück zum Zitat 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.CrossRef 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.CrossRef
97.
Zurück zum Zitat 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. 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.
99.
Zurück zum Zitat Johannessen CM, Boehm JS, Kim SY. COT/MAP3K8 drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468(7326):968–72.PubMedPubMedCentralCrossRef Johannessen CM, Boehm JS, Kim SY. COT/MAP3K8 drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468(7326):968–72.PubMedPubMedCentralCrossRef
101.
Zurück zum Zitat O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol. 2016;13:417–30.PubMedCrossRef O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol. 2016;13:417–30.PubMedCrossRef
103.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
104.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
106.
Zurück zum Zitat Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase-AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.PubMedCrossRef Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase-AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.PubMedCrossRef
107.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
108.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
109.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
110.
Zurück zum Zitat Schopf FH, Biebl MM, Buchner J. The HSP90 chaperone machinery. Nat Rev Mol Cell Biol. 2017;18:345–60.PubMedCrossRef Schopf FH, Biebl MM, Buchner J. The HSP90 chaperone machinery. Nat Rev Mol Cell Biol. 2017;18:345–60.PubMedCrossRef
111.
Zurück zum Zitat Miyata Y, Nakamoto H, Necker L. The therapeutic target Hsp90 and cancer hallmarks. Curr Pharm Des. 2013;19(3):347–65.PubMedCrossRef Miyata Y, Nakamoto H, Necker L. The therapeutic target Hsp90 and cancer hallmarks. Curr Pharm Des. 2013;19(3):347–65.PubMedCrossRef
112.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
113.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
114.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
115.
Zurück zum Zitat 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. 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.
116.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
117.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
Metadaten
Titel
BRAF and MEK Inhibitors: Use and Resistance in BRAF-Mutated Cancers
verfasst von
Jaquelyn N. Sanchez
Ton Wang
Mark S. Cohen
Publikationsdatum
01.04.2018
Verlag
Springer International Publishing
Erschienen in
Drugs / Ausgabe 5/2018
Print ISSN: 0012-6667
Elektronische ISSN: 1179-1950
DOI
https://doi.org/10.1007/s40265-018-0884-8

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