Six first-line tyrosine kinase inhibitors reveal novel inhibition potential for the EGFR S768I mutation

Abstract

Lung cancer, the leading cause of cancer-related mortality, is the most commonly diagnosed cancer. Tyrosine kinase inhibitors (TKIs) are considered a drug-targeted therapy for non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, limited data are available involving the activity of EGFR TKIs against rare EGFR mutations. Here, based on an endogenous EGFR-depleted cell Line H3255 by CRISPR, H3255 cells with rare mutant EGFR^S768I and compound mutations EGFR^S768I+L858R were tested using cell proliferation assay, cytotoxicity, membrane potential, flow cytometry and Western blot analysis. We conducted cytotoxicity screening of EGFR mutations on six front-line TKIs based on first-, second-, and third-generation TKIs (afatinib, dacomitinib, osimertinib, erlotinib, gefitinib, and icotinib). The results showed that the sensitivity of these mutants containing rare variants EGFR^S768I to six front-line TKIs was enriched in the irreversible TKI cytotoxicity assays by determining their change in cytotoxicity, apoptosis, cell proliferation and signal pathway factors. Importantly, the variants harboring EGFR^L858R (H3255), EGFR^S768I (H3255^S768I) and EGFR^S768I+L858R (H3255^S768I+L858R) were sensitive to six TKIs and induced cytotoxicity through different pathways. Moreover, the compound mutations EGFR^S768I+L858R showed more TKI resistance than EGFR^S768I mutation and EGFR^L858R mutation. We present a comprehensive reference for the sensitivity of EGFR^S768I variants to six front-line TKIs. For patients with the EGFR S768I mutation and compound mutations EGFR^S768I+L858R, six first-line TKIs appear to be reasonable therapeutic options.

Keywords: Cytotoxicity; EGFR S768I mutation; Lung adenocarcinoma; Tyrosine kinase inhibitor.