title: Influences of BRAF Inhibitors on the Immune Microenvironment and the Rationale for Combined Molecular and Immune Targeted Therapy.
abstract: The identification of key driver mutations in melanoma has led to the development of targeted therapies aimed at BRAF and MEK, but responses are often limited in duration. There is growing evidence that MAPK pathway activation impairs antitumor immunity and that targeting this pathway may enhance responses to immunotherapies. There is also evidence that immune mechanisms of resistance to targeted therapy exist, providing the rationale for combining targeted therapy with immunotherapy. Preclinical studies have demonstrated synergy in combining these strategies, and combination clinical trials are ongoing. It is, however, becoming clear that additional translational studies are needed to better understand toxicity, proper timing, and sequence of therapy, as well as the utility of multidrug regimens and effects of other targeted agents on antitumor immunity. Insights gained through translational research in preclinical models and clinical studies will provide mechanistic insight into therapeutic response and resistance and help devise rational strategies to enhance therapeutic responses.
authors.affiliation: Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1400 Holcombe Blvd, Unit 463, Houston, TX, 77030, USA.
authors.forename: Sangeetha M
authors.initials: SM
authors.lastname: Reddy
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Reuben
authors.affiliation: Department of Surgical Oncology, Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. jwargo@mdanderson.org.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects*; D007167:Immunotherapy; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; Checkpoint blockade; Combination therapy; MEK; Melanoma; Targeted therapy