title: Strategies for Overcoming Resistance in Tumours Harboring BRAF Mutations.
abstract: The development of resistance to previously effective treatments has been a challenge for health care providers and a fear for patients undergoing cancer therapy. This is an unfortunately frequent occurrence for patients undergoing targeted therapy for tumours harboring the activating V600E mutation of theBRAFgene. Since the initial identification of theBRAFmutation in 2002, a series of small molecular inhibitors that target the BRAFV600E have been developed, but intrinsic and acquired resistance to these drugs has presented an ongoing challenge. More recently, improvements in therapy have been achieved by combining the use of BRAF inhibitors with other drugs, such as inhibitors of the downstream effector mitogen activated protein kinase (MAPK)/extracellular-signal regulated kinase (ERK) kinase (MEK). Despite improved success in response rates and in delaying resistance using combination therapy, ultimately, the acquisition of resistance remains a concern. Recent research articles have shed light on some of the underlying mechanisms of this resistance and have proposed numerous strategies that might be employed to overcome or avoid resistance to targeted therapies. This review will explore some of the resistance mechanisms, compare what is known in melanoma cancer to colorectal cancer, and discuss strategies under development to manage the development of resistance.
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada. nourah-m-obaid@Dal.Ca.
authors.forename: Nourah Mohammad
authors.initials: NM
authors.lastname: Obaid
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada. kbedard@gmail.com.
authors.forename: Karen
authors.initials: K
authors.lastname: Bedard
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada. huangw@nshealth.ca.|Department of Pathology, Nova Scotia Health Authority, Halifax, NS B3H 1V8, Canada. huangw@nshealth.ca.
authors.forename: Weei-Yuarn
authors.initials: WY
authors.lastname: Huang
mesh_terms: D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D003062:Codon; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003062:Codon; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; acquired resistance