Journal
ONCOTARGET
Volume 8, Issue 44, Pages 78174-78192Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.19836
Keywords
melanoma; BRAF; MAPK; immunotherapy; CTLA-4
Categories
Funding
- Medical Research Council [MR/L023091/1]
- Cancer Research UK [C30122/A11527, C30122/A157745]
- Academy of Medical Sciences
- Breast Cancer Now [147]
- CR UK/NIHR in England/DoH for Scotland
- Wales and Northern Ireland Experimental Cancer Medicine Centre [C10355/A15587]
- British Skin Foundation [S633]
- British Association of Dermatologists
- Dermatrust
- Guy's and St Thomas's Charity Melanoma Special Fund
- National Institute for Health Research (NIHR) BRC based at Guy's and St Thomas' NHS Foundation Trust and King's College London [ISBRC-1215-20006]
- Academy of Medical Sciences (AMS) [AMS-SGCL10-Josephs, AMS-SGCL6-Papa] Funding Source: researchfish
- Medical Research Council [MR/L006278/1, MR/L023091/1] Funding Source: researchfish
- National Institute for Health Research [CL-2011-17-007, CL-2012-17-005] Funding Source: researchfish
- MRC [MR/L006278/1, MR/L023091/1] Funding Source: UKRI
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Identification of mutations in the gene encoding the serine/threonine-protein kinase, BRAF, and constitutive activation of the mitogen-activated protein kinase (MAPK) pathway in around 50% of malignant melanomas have led to the development and regulatory approval of targeted pathway inhibitor drugs. A proportion of patients are intrinsically resistant to BRAF inhibitors, and most patients who initially respond, acquire resistance within months. In this review, we discuss pathway inhibitors and their mechanisms of resistance, and we focus on numerous efforts to improve clinical benefits through combining agents with disparate modes of action, including combinations with checkpoint inhibitor antibodies. We discuss the merits of combination strategies based on enhancing immune responses or overcoming tumor-associated immune escape mechanisms. Emerging insights into mechanisms of action, resistance pathways and their impact on host-tumor relationships will inform the design of optimal combinations therapies to improve outcomes for patients who currently do not benefit from recent treatment breakthroughs.
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