The pharmacogenomics of drug resistance to protein kinase inhibitors.
Dysregulation of growth factor cell signaling is a major driver of most human cancers. This has led to development of numerous drugs targeting protein kinases, with demonstrated efficacy in the treatment of a wide spectrum of cancers. Despite their high initial response rates and survival benefits, the majority of patients eventually develop resistance to these targeted therapies. This review article discusses examples of established mechanisms of drug resistance to anticancer therapies, including drug target mutations or gene amplifications, emergence of alternate signaling pathways, and pharmacokinetic variation. This reveals a role for pharmacogenomic analysis to identify and monitor for resistance, with possible therapeutic strategies to combat chemoresistance.
Eshelman School of Pharmacy, Center for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC, United States; H. Lee Moffitt Cancer Center and Research Institute, DeBartolo Family Personalized Medicine Institute, Tampa, FL, United States.
Nancy K
NK
Gillis
H. Lee Moffitt Cancer Center and Research Institute, DeBartolo Family Personalized Medicine Institute, Tampa, FL, United States; Xiangya Hospital, Central South University, Changsha, China. Electronic address: Howard.McLeod@moffitt.org.
Howard L
HL
McLeod
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002999:Clone Cells; D055870:Drug Chronotherapy; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D066246:ErbB Receptors
Cancer; Pharmacogenetics; Pharmacogenomics; Resistance; Somatic mutations