Adaptive resistance mechanisms to mTOR inhibitor in lung squamous cell carcinoma

Resistance to small molecule inhibitors targeting key metabolic pathways in lung tumors remains a significant challenge in personalized cancer therapy. In this study, we investigated the mechanisms of resistance to the small molecule mTOR inhibitor TAK228 across lung squamous cell carcinoma (LUSC) models, including cell lines, xenografts, and patient-derived xenografts (PDXs). Our findings reveal that LUSC cells adapt to mTOR inhibition by engaging macropinocytosis, a form of endocytosis that facilitates enhanced uptake of extracellular nutrients, thereby increasing amino acid availability. Co-inhibition of both mTOR and macropinocytosis using small molecule inhibitors effectively reduced tumor growth. Additionally, we identified angiogenesis as a key mechanism limiting the efficacy of mTOR inhibition in vivo. Notably, inhibiting angiogenesis in combination with inhibitors of mTOR and macropinocytosis reduced tumor growth in xenografts and PDXs. Moreover, prolonged treatment of LUSC PDXs with TAK228 and the glutaminase inhibitor CB-839 led to upregulation of vascularization, which coincided with a rebound in tumor growth despite continued therapeutic administration. These findings highlight adaptive resistance mechanisms to small molecule inhibitors that target key metabolic pathways, lending insight into potential future clinical strategies for the treatment of LUSC.