Macropinocytosis Renders a Subset of Pancreatic Tumor Cells Resistant to mTOR Inhibition

Abstract

Summary: Pancreatic ductal adenocarcinoma (PDAC) features a near-universal mutation in KRAS. Additionally, the tumor suppressor PTEN is lost in ∼10% of patients, and in mouse models, this dramatically accelerates tumor progression. While oncogenic KRAS and phosphatidylinositol 3-kinase (PI3K) cause divergent metabolic phenotypes individually, how they synergize to promote tumor metabolic alterations and dependencies remains unknown. We show that in KRAS-driven murine PDAC cells, loss of Pten strongly enhances both mTOR signaling and macropinocytosis. Protein scavenging alleviates sensitivity to mTOR inhibition by rescuing AKT phosphorylation at serine 473 and consequently cell proliferation. Combined inhibition of mTOR and lysosomal processing of internalized protein eliminates the macropinocytosis-mediated resistance. Our results indicate that mTORC2, rather than mTORC1, is an important regulator of protein scavenging and that protein-mediated resistance could explain the lack of effectiveness of mTOR inhibitors in certain genetic backgrounds. Concurrent inhibition of mTOR and protein scavenging might be a valuable therapeutic approach. : Michalopoulou et al. show that in pancreatic cancer cells with oncogenic KRAS and PTEN loss, scavenging of extracellular protein provides resistance against mTOR inhibition. Protein scavenging circumvents mTORC2 signaling by rescuing AKT phosphorylation. Additional treatment with AKT or lysosomal inhibitors strongly potentiates the effect of mTOR inhibitors. Keywords: AKT, cancer metabolism, macropinocytosis, metabolic scavenging, mTORC2, pancreatic ductal adenocarcinoma