Background and objectives:
Non-small cell lung cancer (NSCLC) is often caused by EGFR mutations, leading to overactive cell growth pathways. Drug resistance is a significant challenge in
lung cancer treatment, affecting
therapy effectiveness and patient survival. However, combining drugs in research shows promise in addressing or delaying resistance, offering a more effective approach to
cancer treatment. In this study, we investigated the potential alterations in the apoptotic pathway in A549 cells induced by a combined targeted
therapy using
tyrosine kinase inhibitors (TKIs)
olmutinib and
poziotinib, focusing on cell proliferation, differential gene expression, and in silico analysis of apoptotic markers. Methods: A combined targeted
therapy involving
olmutinib and
poziotinib was investigated for its impact on the apoptotic pathway in A549 cells. Cell proliferation, quantitative differential gene expression, and in silico analysis of apoptotic markers were examined. A549 cells were treated with varying concentrations (1, 2.5, and 5 μM) of
poziotinib,
olmutinib, and their combination. Results: Treatment with
poziotinib,
olmutinib, and their combination significantly reduced cell proliferation, with the most pronounced effect at 2.5 μM (p < 0.005). A synergistic antiproliferative effect was observed with the combination of
poziotinib and
olmutinib (p < 0.0005). Quantitative differential gene expression showed synergistic action of the
drug combination, impacting key apoptotic genes including STK-11, Bcl-2, Bax, and the Bax/Bcl-2 ratio. In silico analysis revealed direct interactions between EGFR and ERBB2 genes, accounting for 77.64% of their interactions, and 8% co-expression with downstream apoptotic genes. Molecular docking indicated strong binding of
poziotinib and
olmutinib to extrinsic and intrinsic apoptotic pathway markers, with binding energies of -9.4 kcal/mol and -8.5 kcal/mol, respectively, on interacting with STK-11. Conclusions: Combining
poziotinib and
olmutinib therapies may significantly improve drug tolerance and conquer drug resistance more effectively than using them individually in
lung cancer patients, as suggested by this study's mechanisms.