Macropinocytosis and vascularization detrmine response to mTOR inhibitors in lung squamous cell carcinomas

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) cell lines, xenograft models, 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, prolonged treatment of PDXs with TAK228 and the glutaminase inhibitor CB-839 led to upregulation of vascularization, which coincided with a rebound in tumor growth despite the continued presence of both inhibitors. These findings highlight adaptive mechanisms that contribute to resistance to targeted therapies and provide insight into potential clinical strategies to overcome resistance in lung cancer.