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Current Oncology Reports
Published in: Current Oncology Reports 6/2011

01-12-2011 | Melanoma (Kim A. Margolin, Section Editor)

The “SWOT” of BRAF Inhibition in Melanoma: RAF Inhibitors, MEK Inhibitors or Both?

Authors: Moriah H. Nissan, David B. Solit

Published in: Current Oncology Reports | Issue 6/2011

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Abstract

Activating mutations in the BRAF gene are among the most prevalent kinase mutations in human cancer. BRAF mutations are most frequent in patients with melanoma where they occur in approximately 50% of patients with advanced disease. Remarkable clinical activity has recently been reported with highly selective RAF inhibitors in melanoma patients whose tumors harbor V600E BRAF mutations. The response rates of RAF inhibitors in patients with BRAF-mutant melanomas far exceed the activity level of any prior therapy studied in this disease. The results suggest that we have entered an era of personalized therapy for patients with metastatic melanoma in which treatment selection will be guided by BRAF mutational status. This review will discuss the strengths, weaknesses, opportunities and threats ("SWOT") of developing RAF and MEK selective inhibitors as anti-cancer therapies, recent insights into the mechanisms of intrinsic and acquired resistance to these agents, and current efforts to develop mechanism-based combination therapies.
Literature
1.
2.
3.
Pratilas CA et al. (V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc Natl Acad Sci USA. 2009;106(11):4519–24.PubMedCrossRef
4.
Board RE et al. Detection of BRAF mutations in the tumour and serum of patients enrolled in the AZD6244 (ARRY-142886) advanced melanoma phase II study. Br J Cancer. 2009;101(10):1724–30.PubMedCrossRef
5.
Dong C et al. SOS phosphorylation and disassociation of the Grb2-SOS complex by the ERK and JNK signaling pathways. J Biol Chem. 1996;271(11):6328–32.CrossRef
6.
Eblen ST et al. Mitogen-activated protein kinase feedback phosphorylation regulates MEK1 complex formation and activation during cellular adhesion. Mol Cell Biol. 2004;24(6):2308–17.PubMedCrossRef
7.
Northwood IC et al. Isolation and characterization of two growth factor-stimulated protein kinases that phosphorylate the epidermal growth factor receptor at threonine 669. J Biol Chem. 1991;266(23):15266–76.PubMed
8.
Vigil D et al. Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer. 2010;10(12):842–57.PubMedCrossRef
9.
Weber CK et al. Active Ras induces heterodimerization of cRaf and BRaf. Cancer Res. 2001;61(9):3595–8.PubMed
10.
Wan PT et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116(6):855–67.PubMedCrossRef
11.
Owens DM, Keyse SM. Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene. 2007;26(22):3203–13.PubMedCrossRef
12.
Kim HJ, Bar-Sagi D. Modulation of signalling by Sprouty: a developing story. Nat Rev Mol Cell Biol. 2004;5(6):441–50.PubMedCrossRef
13.
Pratilas CA, Solit DB. Targeting the mitogen-activated protein kinase pathway: physiological feedback and drug response. Clin Cancer Res. 2010;16(13):3329–34.PubMedCrossRef
14.
Chitale D et al. An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors. Oncogene. 2009;28(31):2773–83.PubMedCrossRef
15.
16.
Curtin JA et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353(20):2135–47.PubMedCrossRef
17.
Samowitz WS et al. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res. 2005;65(14):6063–9.PubMedCrossRef
18.
Dhomen N et al. Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell. 2009;15(4):294–303.PubMedCrossRef
19.
20.
Vakiani E, Yantiss RK. Pathologic features and biologic importance of colorectal serrated polyps. Adv Anat Pathol. 2009;16(2):79–91.PubMedCrossRef
21.
Dankort D et al. A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors. Genes Dev. 2007;21(4):379–84.PubMedCrossRef
22.
Patton EE et al. BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Curr Biol. 2005;15(3):249–54.PubMedCrossRef
23.
Dankort D et al. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet. 2009;41(5):544–52.PubMedCrossRef
24.
Wilhelm SM et al. BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64(19):7099–109.PubMedCrossRef
25.
Clark JW et al. Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43–9006, in patients with advanced, refractory solid tumors. Clin Cancer Res. 2005;11(15):5472–80.PubMedCrossRef
26.
Bollag G et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010;467(7315):596–9.PubMedCrossRef
27.
•• Flaherty KT et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809–19. This manuscript reports the first in-patient phase 1 trial of the RAF inhibitor PLX4032. In this trial, PLX4032 had an 81% response rate in patients with melanoma whose tumors expressed a BRAF mutation.PubMedCrossRef
28.
Chapman PB, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011.
29.
Joseph EW et al. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc Natl Acad Sci USA. 2010;107(33):14903–8.PubMedCrossRef
30.
• Poulikakos PI et al. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464(7287):427–30. This study demonstrates that the paradoxical activation of MAPK pathway signaling by PLX4032 observed in BRAF wild-type cells is mediated by the formation of RAF dimers.PubMedCrossRef
31.
Heidorn SJ et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140(2):209–21.PubMedCrossRef
32.
Hatzivassiliou G et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464(7287):431–5.PubMedCrossRef
33.
Halaban R et al. PLX4032, a selective BRAF(V600E) kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells. Pigment Cell Melanoma Res. 2010;23(2):190–200.PubMedCrossRef
34.
LoRusso PM et al. Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clin Cancer Res. 2010;16(6):1924–37.PubMedCrossRef
35.
Kefford R, Arkenau H, Brown MP, Millward M, Infante JR, Long GV, Ouellet D, Curtis M, Lebowitz PF, Falchook GS. Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors. J Clin Oncol 2010;28.
36.
Solit DB et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2006;439(7074):358–62.PubMedCrossRef
37.
Pratilas CA et al. Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res. 2008;68(22):9375–83.PubMedCrossRef
38.
Halilovic E et al. PIK3CA mutation uncouples tumor growth and cyclin D1 regulation from MEK/ERK and mutant KRAS signaling. Cancer Res. 2010;70(17):6804–14.PubMedCrossRef
39.
Lorusso PM et al. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol. 2005;23(23):5281–93.PubMedCrossRef
40.
Brown AP et al. Pharmacodynamic and toxicokinetic evaluation of the novel MEK inhibitor, PD0325901, in the rat following oral and intravenous administration. Cancer Chemother Pharmacol. 2007;59(5):671–9.PubMedCrossRef
41.
Dummer R, Robert C, Chapman PB, Sosman JA, Middleton M, Bastholt L, Kemsley K, Cantarini MV, Morris C, Kirkwood JM. AZD6244 (ARRY-142886) vs temozolomide (TMZ) in patients (pts) with advanced melanoma: an open-label, randomized, multicenter, phase II study. J Clin Oncol 2008;26.
42.
Tzekova V, Cebotaru C, Ciuleanu TE, Damjanov D, Ganchev H, Kanarev V, Stella PJ, Sanders N, Pover G, Hainsworth JD. Efficacy and safety of AZD6244 (ARRY-142886) as second/third-line treatment of patients (pts) with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2008;26(15S).
43.
Lang I, Adenis A, Boer K, Escudero P, Kim T, Valladares M, Sanders N, Pover G, Douillard J. AZD6244 (ARRY-142886) versus capecitabine (CAP) in patients (pts) with metastatic colorectal cancer (mCRC) who have failed prior chemotherapy. J Clin Oncol 2008;26.
44.
Infante JR, Fecher LA, Nallapareddy S, Gordon Ms, Flaherty KT, Cox DS, DeMarini DJ, Morris SR, Burris HA, Messersmith WA. Safety and efficacy results from the first-in-human study of the oral MEK 1/2 inhibitor GSK1120212. J Clin Oncol 2010;28(15s).
45.
Engelman JA et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med. 2008;14(12):1351–6.PubMedCrossRef
46.
She QB et al. 4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors. Cancer Cell. 2010;18(1):39–51.PubMedCrossRef
47.
Solit D, Sawyers CL. Drug discovery: how melanomas bypass new therapy. Nature. 2010;468(7326):902–3.PubMedCrossRef
48.
Whittaker S et al. Gatekeeper mutations mediate resistance to BRAF-targeted therapies. Sci Transl Med. 2010;2(35):35ra41.PubMedCrossRef
49.
Nazarian R et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468(7326):973–7.PubMedCrossRef
50.
Wagle N et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol 2011.
51.
Montagut C et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res. 2008;68(12):4853–61.PubMedCrossRef
52.
Johannessen CM et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468(7326):968–72.PubMedCrossRef
53.
Villanueva J et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell. 2010;18(6):683–95.PubMedCrossRef
54.
Gopal YN et al. Basal and treatment-induced activation of AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in Braf-mutant human cutaneous melanoma cells. Cancer Res. 2010;70(21):8736–47.PubMedCrossRef
55.
Hodi FS et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.PubMedCrossRef
Metadata
Title
The “SWOT” of BRAF Inhibition in Melanoma: RAF Inhibitors, MEK Inhibitors or Both?
Authors
Moriah H. Nissan
David B. Solit
Publication date
01-12-2011
Publisher
Current Science Inc.
Published in
Current Oncology Reports / Issue 6/2011
Print ISSN: 1523-3790
Electronic ISSN: 1534-6269
DOI
https://doi.org/10.1007/s11912-011-0198-4

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