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Strategies to overcome acquired resistances conferred by mutations in the kinase domain of EGFR.

Deregulation of EGFR is involved in the development of many cancers. The inhibition of EGFR kinase activity has been clinically validated as a promising approach for the treatment of non-small-cell lung cancer (NSCLC). However, all NSCLC patients who initially benefited from first-generation EGFR inhibitors eventually develop drug resistance. A point mutation at the gatekeeper position, T790M in EGFR kinase domain accounts for more than 50% of acquired resistance. Therefore, second- and third-generation EGFR inhibitors have been developed to overcome the resistance conferred by the gatekeeper mutation. This review has highlighted recent advances in overcoming acquired resistance for the development of each generation of EGFR inhibitors along with their potential issues, and urgent quest for the development of new generation of EGFR inhibitors.