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.

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.

CUDC­101 is a potential target inhibitor for the EGFR­overexpression bladder cancer cells.

Bladder cancer is one of the most common urological malignancies worldwide. The molecular mechanism underlying its development is complex, but its carcinogenesis has been proposed to occur with cell proliferation and resistance to apoptosis, driven by the signaling activity of abundant EGFR and receptor tyrosine­protein kinase erbB­2. In the present study, T24 bladder cancer cell lines with EGFR­overexpression were constructed, before the multi­target inhibitor CUDC­101 was used to investigate its potential as a targeted therapeutic agent for bladder cancer using chemosensitivity methods. The results showed that CUDC­101 induced cytotoxic effects, inhibited growth vitality and proliferation in a dose­dependent manner. CUDC­101 also altered the skeletal morphology and microfilament structure, while blocking cell cycle progression and causing apoptosis. These results supported the proposed cytotoxic effects of CUDC­101, in addition to its inhibitory effects on cell division and proliferation in EGFR­overexpressing bladder cancer cells. Therefore CUDC­101 may to be a potential therapeutic option for the treatment of bladder cancer.

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

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 EGFRS768I and compound mutations EGFRS768I+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 EGFRS768I 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 EGFRL858R (H3255), EGFRS768I (H3255S768I) and EGFRS768I+L858R (H3255S768I+L858R) were sensitive to six TKIs and induced cytotoxicity through different pathways. Moreover, the compound mutations EGFRS768I+L858R showed more TKI resistance than EGFRS768I mutation and EGFRL858R mutation. We present a comprehensive reference for the sensitivity of EGFRS768I variants to six front-line TKIs. For patients with the EGFR S768I mutation and compound mutations EGFRS768I+L858R, six first-line TKIs appear to be reasonable therapeutic options.