Journal
CANCER
Volume 123, Issue -, Pages 2118-2129Publisher
WILEY
DOI: 10.1002/cncr.30435
Keywords
BRAF inhibitors; immunotherapy; melanoma; mitogen-activated protein kinase (MAPK) pathway; mitogen-activated protein kinase kinase (MEK) inhibitors; phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway; targeted therapy
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Funding
- National Health and Medical Research Council
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The identification of driver mutations in melanoma has changed the field of cancer treatment. BRAF and NRAS mutations are predominant in melanoma and lead to overactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways. Selective inhibitors targeting key effectors of the MAPK pathway have revolutionized the treatment of patients with advanced metastatic BRAF-mutant melanoma. However, resistance to therapy is almost universal and remains a major challenge in clinical care, with the majority of patients progressing within 1 year. Dissecting the mechanisms of resistance to targeted therapies may offer new insights into strategies for overcoming resistance. This review describes the efficacy of therapies targeting the MAPK and PI3K/AKT signaling pathways in melanoma, details the mechanisms contributing to drug resistance, and discusses current approaches to improving outcomes further. (c) 2017 American Cancer Society.
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