Resistance to combination BRAF and MEK inhibition in metastatic melanoma: Where to next?

doi:10.1016/j.ejca.2016.04.005

European Journal of Cancer

Volume 62, July 2016, Pages 76-85

https://doi.org/10.1016/j.ejca.2016.04.005 Get rights and content

Highlights

•
BRAF and MEK inhibitors have improved survival in BRAF-mutant metastatic melanoma.
•
Unfortunately resistance develops in the majority of patients at approximately 1 year.
•
Potentially targetable resistance mechanisms are discussed.
•
Combination of BRAF/MEK inhibitors with other drugs is likely to be needed to overcome resistance.

Abstract

Treatment of BRAF-mutant metastatic melanoma with mitogen-activated protein kinase (MAPK) pathway targeted therapies (BRAF/MEK inhibitors) and immune checkpoint inhibitors has revolutionised management and improved outcomes for patients with advanced stage disease. However, acquired resistance to MAPK inhibitor therapy develops in the majority of patients at approximately 12 months and multiple mechanisms lead to resistance. Understanding the mechanisms of resistance is therefore critical for the development of more effective therapeutic strategies in BRAF-mutant melanoma. Recently, several distinct mechanisms of resistance to BRAF-inhibition have been proposed based on data obtained in experimental melanoma cell models and small series of human tumour samples. These include reactivation of the MAPK pathway resulting in continued extracellular signal-regulated kinase activation and activation of parallel signalling pathways including the PI3K-mTOR (phosphoinositide 3-kinase–mammalian target of rapamycin) pathway. Alterations in how the cells of the immune system respond to melanoma cells treated with targeted therapy may also influence response and progression. In this review, we discuss these mechanisms and identify potential therapeutic strategies to overcome resistance which, in turn, will lead to improved outcomes for patients with metastatic melanoma.

Introduction

Melanoma is the most lethal form of skin cancer and its incidence continues to increase worldwide [1]. Until recently, the 5-year survival for patients with advanced melanoma (including both lymph node and other metastases) was only 16% (Surveillance, Epidemiology, and End Results (SEER) data 2011), and no drug therapy improved overall survival (OS). Since 2010, both selective kinase and immune checkpoint inhibitors have demonstrated survival benefits (reviewed in [2]), and have been approved for use in patients with metastatic melanoma in many countries around the world.

Approximately 40% of melanomas carry oncogenic BRAF mutations that constitutively activate the mitogen-activated protein kinase (MAPK) [3]. The most common BRAF mutation is V600E, which accounts for approximately 75–90% of the BRAF mutations identified in melanoma [2]. Pre-clinical studies showed that BRAF^V600-mutant melanomas require MAPK signalling for their survival (reviewed in http://www.sciencedirect.com/science/article/pii/S2211124713004646 [4]) and phase III clinical trials confirmed that inhibition of BRAF alone, or the combined inhibition of BRAF and its downstream target, MEK, improved the OS of patients with advanced BRAF-mutant melanoma [5], [6], [7], [8], [9]. Based on these trials, the BRAF inhibitors (BRAFi) dabrafenib and vemurafenib as single agents, and dabrafenib combined with the MEK inhibitor trametinib are now approved for the treatment of metastatic BRAF mutant melanoma (reviewed in [2]).

In this review, we describe the data leading to the approval of BRAF/MEK inhibitors (BRAF/MEKi) for BRAF^V600-mutant metastatic melanoma, and we explore the three major effectors of BRAF/MEK inhibitor resistance which are potentially targetable and propose new treatment strategies to further improve outcomes for patients with BRAF-mutated metastatic melanoma.

Section snippets

Approved targeted therapies in BRAF-mutated melanoma

Two BRAFi have been approved for the treatment of BRAF-mutated metastatic melanoma. Vemurafinib was the first targeted agent to be approved worldwide as first line treatment for BRAF^V600-mutated metastatic melanoma after the landmark phase III study (BRIM-3) at first interim analysis showed that vemurafenib resulted in a significant improvement in progression-free survival (PFS) compared with dacarbazine chemotherapy (hazard ratio [HR] 0.26; p < 0.001, median PFS 5.8 versus 1.6 months,

Potentially targetable resistance mechanisms to targeted therapy

Acquisition of melanoma resistance to BRAFi occurs after a median of 6–8 months in 50% of patients on vemurafenib or dabrafenib monotherapy [5], [6]. Although resistance to combined BRAFi and MEKi therapy is delayed compared to treatment with the single agents, resistance remains a significant problem [14]. Interestingly, in contrast to the acquired resistance observed with other small molecule kinase inhibitors, such as imatinib in chronic myeloid leukaemia and epidermal growth factor receptor

Conclusions

There has been dramatic progress in improving clinical outcomes for patients with melanoma in the past 5 years. Combined treatment with BRAF and MEK inhibitors has significantly improved OS but resistance continues to be problematic. In this review we have discussed three therapeutic strategies that may overcome or delay resistance to MAPKi based on both the changes observed in melanoma tissue early during treatment and the known resistance mechanisms. Clinical trials using agents which target

Conflict of interest statement

G.V.L. is a consultant advisor to Amgen, BMS, MERCK MSD, Novartis, Provectus, Roche. Other authors have no conflicts of interest.

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ReviewResistance to combination BRAF and MEK inhibition in metastatic melanoma: Where to next?

Highlights

Abstract

Introduction

Section snippets

Approved targeted therapies in BRAF-mutated melanoma

Potentially targetable resistance mechanisms to targeted therapy

Conclusions

Conflict of interest statement

Lancet Oncol

Lancet

Lancet

Biochem Pharmacol

Cancer Cell

Mol Oncol

Cancer Cell

Biochem Pharmacol

Cancer Cell

J Invest Dermatol

Curr Opin Pharmacol

Ann Oncol

Semin Oncol

GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]

Dividing and conquering: controlling advanced melanoma by targeting oncogene-defined subsets

Clin Exp Metastasis

BRAF targeted therapy changes the treatment paradigm in melanoma

Nat Rev Clin Oncol

Improved survival with vemurafenib in melanoma with BRAF V600E mutation

N Engl J Med

Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma

N Engl J Med

Improved overall survival in melanoma with combined dabrafenib and trametinib

N Engl J Med

BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact

Clin Cancer Res

Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy

Cancer Discov

The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma

Cancer Discov

Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations

N Engl J Med

Overall survival and durable responses in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib combined with trametinib

J Clin Oncol

RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors

N Engl J Med

Combined vemurafenib and cobimetinib in BRAF-mutated melanoma

N Engl J Med

Gatekeeper mutations mediate resistance to BRAF-targeted therapies

Sci Transl Med

RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)

Nature

Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance

Nat Commun

Preexisting MEK1P124 mutations diminish response to BRAF inhibitors in metastatic melanoma patients

Clin Cancer Res

MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition

Cancer Discov

COT drives resistance to RAF inhibition through MAP kinase pathway reactivation

Nature

Rizos H.Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma

Nat Commun

A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition

Cancer Discov

Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma

J Clin Oncol

Antitumor activity of the ERK inhibitor SCH722984 against BRAF mutant

NRAS mutant and wild-type melanoma.Mol Cancer

Review
Resistance to combination BRAF and MEK inhibition in metastatic melanoma: Where to next?