title: Mechanisms of Drug Resistance in Melanoma.
abstract: Metastatic melanoma is associated with poor outcome and is largely refractory to the historic standard of care. In recent years, the development of targeted small-molecule inhibitors and immunotherapy has revolutionised the care and improved the overall survival of these patients. Therapies targeting BRAF and MEK to block the mitogen-activated protein kinase (MAPK) pathway were the first to show unprecedented clinical responses. Following these encouraging results, antibodies targeting immune checkpoint inhibition molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death (PD)-1, and PD-ligand1(PD-L1) demonstrated sustained tumour regression in a significant subset of patients by enabling an anti-tumour immunologic response. Despite these landmark changes in practice, the majority of patients are either intrinsically resistant or rapidly acquire resistance to MAPK pathway inhibitors and immune checkpoint blockade treatment. The lack of response can be driven by mutations and non-mutational events in tumour cells, as well as by changes in the surrounding tumour microenvironment. Common resistance mechanisms bypass the dependence of tumour cells on initial MAPK pathway driver mutations during targeted therapy, and permit evasion of the host immune system to allow melanoma growth and survival following immunotherapy. This highlights the requirement for personalised treatment regimens that take into account patient-specific genetic and immunologic characteristics. Here we review the mechanisms by which melanomas display intrinsic resistance or acquire resistance to targeted therapy and immunotherapy.
authors.affiliation: Skin Cancer and Ageing, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Winder
authors.affiliation: Skin Cancer and Ageing, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK. Amaya.Viros@cruk.manchester.ac.uk.|Salford Royal NHS Foundation Trust, Manchester, UK. Amaya.Viros@cruk.manchester.ac.uk.
authors.forename: Amaya
authors.initials: A
authors.lastname: Virós
mesh_terms: D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007167:Immunotherapy; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000188:drug therapy*; D058990:Molecular Targeted Therapy; D061026:Programmed Cell Death 1 Receptor; D047428:Protein Kinase Inhibitors; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D060908:CTLA-4 Antigen; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D047428:Protein Kinase Inhibitors
keywords: Acquired resistance; BRAF inhibitor; Checkpoint inhibitor; Immunotherapy; Intrinsic resistance; MAPK pathway; MEK inhibitor; Melanoma; Targeted therapy