title: Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations.
abstract: Identifying activating EGFR mutations is a useful predictive strategy that helps select a population of advanced non-small-cell lung cancer (NSCLC) patients for treatment with EGFR tyrosine kinase inhibitors (TKIs). Patients with sensitizing EGFR mutations (predominantly an in-frame deletion in exon 19 and an L858R substitution) are highly responsive to first-generation EGFR TKIs, such as gefitinib and erlotinib, and show improved progression-free survival without serious side effects. However, all patients with activating EGFR mutations who are initially responsive to EGFR TKIs eventually develop acquired resistance after a median progression-free survival of 10-16 months, followed by disease progression. Moreover, ~20%-30% of NSCLC patients have no objective tumor regression on initial EGFR TKI treatment, although they harbor an activating EGFR mutation. These patients represent an NSCLC subgroup that is defined as having intrinsic or primary resistance to EGFR TKIs. Different mechanisms of acquired EGFR TKI resistance have been identified, and several novel compounds have been developed to reverse acquired resistance, but little is known about EGFR TKI intrinsic resistance. In this review, we summarize the latest findings involving mechanisms of intrinsic resistance to EGFR TKIs in advanced NSCLC with activating EGFR mutations and present possible therapeutic strategies to overcome this resistance.
authors.affiliation: Department of Oncology, General Hospital, Jinan Command of the People's Liberation Army, Jinan, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Oncology, General Hospital, Jinan Command of the People's Liberation Army, Jinan, People's Republic of China.
authors.forename: Baocheng
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Oncology, General Hospital, Jinan Command of the People's Liberation Army, Jinan, People's Republic of China.
authors.forename: Huili
authors.initials: H
authors.lastname: Chu
authors.affiliation: Department of Oncology, General Hospital, Jinan Command of the People's Liberation Army, Jinan, People's Republic of China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Yao
keywords: EGFR TKIs; EGFR mutation; NSCLC; T790M; intrinsic resistance