Abstract 422: Cell intrinsic determinants of response to mTOR based therapy
Authors: Momcilovic Milica , Shackelford David 
Published: April 2023

Abstract
Lung cancer is a leading cause of cancer death with estimated 135,000 deaths in 2021. Recent developments in the immunotherapy field have expanded treatment options available to lung cancer patients, with most patients now receiving checkpoint inhibitors as part of the first line therapy. However, while durable responses have been achieved in 20-30% of patients, the majority of patients inevitably progress on immunotherapy, chemo-immunotherapy or targeted therapy regiments. With five year survival at ~10% there is an urgent need for novel strategies for the treatment of lung cancer. Lung squamous cell carcinoma (LUSC) is an aggressive subtype of non-small cell lung cancer characterized by poor prognosis. LUSC are highly metabolically active, with uptake of high levels of glucose and glutamine supporting their growth and proliferation. In addition to fueling tumor cell growth, high levels of glycolysis and glutaminolysis help create unfavorable tumor microenvironment, contributing to the poor response to immunotherapy. The Cancer Genome Atlas (TCGA) revealed that LUSC have a high mutational burden but few mutations in oncogenes that can be targeted with selective inhibitors. This lack of clear genetic drivers in LUSC has resulted in a lack of targeted therapies for these patients. We have demonstrated that catalytic mTOR kinase inhibitor TAK228 inhibits glycolysis in LUSC cell lines, in xenografts, in patient derived xenografts and genetically engineered mouse models. However, despite inhibiting active mTOR pathway and lowering glucose uptake, LUSC tumors were able to maintain high levels of proliferation. Our work showed that tumors were able to adapt to prolonged treatment with TAK228 by relying on glutaminolysis. Inhibiting both mTOR and GLS, a key enzyme in glutaminolysis, resulted in reduced proliferation index and lower tumor volume. However, while combination therapy halted tumor growth, there was a lack of tumor regression. Therefore, tumors are poised to further adapt to combination therapy. Here we show that upregulation of lysosomal function supports adaptation to TAK228 therapy in LUSC by supporting macropinocytosis, a form of endocytosis that allows cancer cells to uptake extracellular fluids and further process solutes and macromolecules in lysosomes, leading to the release of amino acids inside the cytoplasm. This suggests that macropinocytosis might be a mechanism that is utilized by LUSC in order to escape mTORi therapy, where upon treatment with mTOR inhibitors, lysosomal catabolism of macropinocytosed proteins increases, allowing tumor cells to increase their proliferation.Resistance to targeted therapies is a major hurdle to achieving effective therapies in multiple cancer types. Identifying ways to overcome resistance to targeted therapies would allow for longer and more efficient therapeutic response for larger number of patients, ultimately leading to longer survival and better quality of life.
Citation Format: Milica Momcilovic, David Shackelford. Cell intrinsic determinants of response to mTOR based therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 422.