title: Strategies to overcome resistance to tyrosine kinase inhibitors in non-small-cell lung cancer.
abstract: The use of molecularly targeted agents has dramatically improved the prognosis of defined subsets of patients with non-small-cell lung cancer harboring somatically activated oncogenes, such as mutant EGFR or rearranged ALK. However, after initial marked responses to EGFR or ALK tyrosine kinase inhibitors (TKIs), almost all patients inevitably progress due to development of acquired resistance. Multiple molecular mechanisms of resistance have been identified; the best characterized are secondary mutations in the tyrosine kinase domain of the oncogene, such as T790M in EGFR and L1196M in ALK, which prevent target inhibition by the corresponding TKI. Other mechanisms include copy number gain of the ALK fusion gene and the activation of bypass signaling pathways that can maintain downstream proliferation and survival signals despite inhibition of the original drug target. Here, the authors provide an overview of the known mechanisms of resistance to TKIs and outline the therapeutic strategies, including new investigational agents and targeted therapies combinations, that have been developed to overcome resistance.
authors.affiliation: Medical Oncology Unit, Human Pathology Department, University of Messina, Messina, Italy.
authors.forename: Mariacarmela
authors.initials: M
authors.lastname: Santarpia
authors.forename: Nuno
authors.initials: N
authors.lastname: Gil
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D011505:Protein-Tyrosine Kinases
keywords: ALK; EGFR; TKI resistance; TKIs; non-small-cell lung cancer