Transcriptomic analysis revealed activation of the TNF-α/NF-κB axis as a potential mechanism of acquired resistance.<h4>Conclusion</h4>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. Here, PIK3CA is linked to non-small cell lung carcinoma.