title: Potential therapeutic strategies to overcome acquired resistance to BRAF or MEK inhibitors in BRAF mutant cancers.
abstract: Recent clinical trials with selective inhibitors of the BRAF and MEK kinases have shown promising results in patients with tumors harboring BRAF V600 mutations. However, as has been observed previously with similarly successful targeted therapies, acquired resistance to these agents is an emerging problem that limits their clinical benefit. Several recent studies from our laboratory and others have investigated the causes of acquired resistance to BRAF and MEK inhibitors, and multiple resistance mechanisms have been identified. Here, we review these mechanisms and suggest that they can be broadly grouped into two main classes: ERK-dependent and ERK-independent. We also propose distinct therapeutic strategies that might be employed to overcome each class of acquired resistance..
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Corcoran
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic / Q000379:methods / Q000639:trends; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D008954:Models, Biological; D050505:Mutant Proteins / Q000235:genetics / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases