The pharmacogenomics of drug resistance to protein kinase inhibitors

• Published in: Drug resistance updates Vol. 28; pp. 28 - 42
• Main Authors: Gillis, Nancy K., McLeod, Howard L.
• Format: Journal Article
• Language: English
• Published: Scotland Elsevier Ltd 01.09.2016
• Subjects: Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Cancer; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Clone Cells; Drug Chronotherapy; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Gene Expression Regulation, Neoplastic; Hematology, Oncology and Palliative Medicine; Humans; Infectious Disease; Molecular Targeted Therapy - methods; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - pathology; Pharmacogenetics; Pharmacogenomics; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinases - genetics; Protein Kinases - metabolism; Resistance; Signal Transduction; Somatic mutations; Resistance; Pharmacogenetics; Somatic mutations; Pharmacogenomics; Cancer
• ISSN: 1368-7646; 1532-2084
• DOI: 10.1016/j.drup.2016.06.008

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.