title: Resistance to combination BRAF and MEK inhibition in metastatic melanoma: Where to next?
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.
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Biomedical Sciences, Macquarie University, 2 Technology Place, Sydney, NSW 2109, Australia; Melanoma Institute Australia, 40 Rocklands Road, Wollstonecraft, NSW 2065, Australia.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Welsh
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Biomedical Sciences, Macquarie University, 2 Technology Place, Sydney, NSW 2109, Australia; Melanoma Institute Australia, 40 Rocklands Road, Wollstonecraft, NSW 2065, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Rizos
authors.affiliation: Melanoma Institute Australia, 40 Rocklands Road, Wollstonecraft, NSW 2065, Australia; The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: Melanoma Institute Australia, 40 Rocklands Road, Wollstonecraft, NSW 2065, Australia; The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: georgina.long@melanoma.org.au.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases
keywords: BRAF inhibition; Immunotherapy; MAPK signalling; MEK inhibition; Melanoma; Resistance