Enhancing Chemotherapeutic Efficacy in Lung Cancer Cells Through Synergistic Targeting of the PI3K/AKT Pathway with Small Molecule Inhibitors

Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality, with resistance to chemotherapy representing a major therapeutic challenge. In this study, we investigated the effects of conventional chemotherapeutics, Cisplatin and 5-fluorouracil (5-FU), in combination with small molecule inhibitors (SMIs) targeting the PI3K/AKT signaling pathway, on NSCLC cell viability. Two NSCLC cell lines, H460 (large cell lung carcinoma) and A549 (adenocarcinoma), both characterized by constitutive activation of PI3K/AKT signaling, were evaluated. A normal human lung fibroblast cell line, MRC-5, was used as a non-cancer control to assess selectivity and exclude cytotoxic effects. Dose–response analyses were performed to determine the optimal concentrations of Cisplatin, 5-FU, the AKT inhibitor MK2206, and the PI3K inhibitor BKM120, both as monotherapies and in combination treatments. We identified a synergistic combination of 5-FU and BKM120 that significantly reduced viability and induced apoptosis in NSCLC cells while sparing MRC-5 cells. Mechanistic studies revealed that apoptosis induction was mediated through the apoptotic pathway regulated by the Bcl-2 family and activation of caspase-3 and caspase-6. These findings highlight the therapeutic potential of combining PI3K/AKT inhibitors with conventional chemotherapy to overcome resistance mechanisms in NSCLC.