Almonertinib and alflutinib show novel inhibition on rare EGFR S768I mutant cells.

PURPOSE: EGFR classical mutations respond well to EGFR tyrosine kinase inhibitors. However, it is uncertain whether currently available EGFR-TKIs are effective against rare EGFR mutations and compound mutations. Herein, the effectiveness of almonertinib and alflutinib, the third-generation tyrosine kinase inhibitors developed in China, on rare EGFR S768I mutations and compound mutations is identified. METHODS: In this study, using CRISPR method, four EGFR S768I mutation cell lines were constructed, and the sensitivity of EGFR to almonertinib and alflutinib was tested, with positive controls being the 1st (gefitinib), 2nd (afatinib), and 3rd (osimertinib) generation drugs. RESULTS: The present results indicate that almonertinib and alflutinib can effectively inhibit cell viability and proliferation in rare EGFR S768I mutations through the ERK or AKT pathways in a time-dependent manner, by blocking the cell cycle and inhibiting apoptosis. CONCLUSIONS: These findings suggest that almonertinib and alflutinib may be potential therapeutic options for non-small cell lung cancer patients with the EGFR S768I mutation.

BDTX-189, a novel tyrosine kinase inhibitor, inhibits cell activity via ERK and AKT pathways in the EGFR C797S triple mutant cells.

The tertiary mutation C797S in the structural domain of the EGFR kinase is a common cause of resistance to third-generation EGFR tyrosine kinase inhibitors (TKIs). In this study, we used a potent, selective and irreversible inhibitor, BDTX-189, to target EGFR C797S triple mutant cells for cell activity. The study constructed the H1975-C797S (EGFR L858R/T790 M/C797S) cell line using the CRISPR/Cas9 method and investigated its potential as a fourth-generation tyrosine kinase inhibitor via chemosensitivity approach. The results demonstrated its ability to induce cytotoxic effects, and inhibit EGFR L858R/T790 M/C797S cell growth and proliferation in a dose-dependent manner. Meanwhile, BDTX-189 reduces the protein phosphorylation levels of EGFR, ERK, and AKT, promoting apoptosis. Furthermore, BDTX-189 not only inhibits common EGFR triple mutations but also effectively inhibits EGFR L858R mutation and EGFR L858R/T790 M mutation. These findings support the cytotoxic effect of BDTX-189 and its inhibitory effect on cell division and proliferation with the EGFR C797S triple mutation.