ArticleTranslational oncology2026
Synergistic effects through targeting the PI3K and IGFR pathways in treating lung cancer carrying activation alterations along the PI3K pathway.
Article in Translational oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
purposeAlterations 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.
methodsWe 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.
resultsGenetic 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.
conclusionConcurrent 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.
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