Synergistic effects through targeting the PI3K and IGFR pathways in treating lung cancer carrying activation alterations along the PI3K pathway.

Alterations in the PI3K/AKT pathway occur in over 60 % of lung squamous cell carcinoma and approximately 20 % of lung adenocarcinoma, driving tumor progression and therapeutic resistance. While PI3K-targeted therapies suppress proliferation in PIK3CA-mutant non-small cell lung cancer (NSCLC), their clinical impact is limited due to compensatory activation of insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) signaling. This study aimed to determine whether dual blockade of PI3K and IR/IGF-1R signaling could overcome this adaptive resistance. We assessed the effects of combining ceritinib, an ALK and IR/IGF-1R inhibitor, with a PI3K/AKT inhibitor in PIK3CA E545K-mutant H460 NSCLC cells. Functional assays included colony formation, wound healing, Matrigel invasion, and Western blot analyses. Therapeutic efficacy was further evaluated in a patient-derived xenograft (PDX) model of lung squamous cell carcinoma harboring the PIK3CA E545K mutation. Transcriptomic profiling using RNA-seq was conducted to identify resistance-associated pathways, and key findings were validated by qRT-PCR. Genetic ablation of PIK3CA markedly reduced proliferation. Dual inhibition of PI3K and IR/IGF-1R signaling resulted in strong synergistic anti-proliferative, anti-migratory, and anti-invasive effects in vitro. In the PDX model, the combination therapy significantly prolonged overall survival without additional systemic toxicity. Transcriptomic analysis revealed activation of the TNF-α/NF-κB axis as a potential mechanism of acquired resistance. Concurrent targeting of PI3K and IR/IGF-1R signaling effectively overcomes adaptive resistance in PIK3CA-mutant NSCLC, supporting the rationale for further clinical evaluation of this combined therapeutic strategy.