Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion
Menée sur des lignées cellulaires d'adénocarcinome canalaire du pancréas et à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel l'inhibition de la fonction lysosomale par la chloroquine sensibilise les cellules cancéreuses au stress de réplication en réduisant le niveau intracellulaire de l'aspartate
Pancreatic cancer is notoriously treatment resistant. These tumors rely on lysosome-dependent recycling pathways to generate substrates for metabolism, which are inhibited by chloroquine (CQ) and its derivatives. However, clinical efficacy of CQ as a monotherapy or combined with standard-of-care regimens has been limited. Using an unbiased kinome screen, we identify replication stress as an induced vulnerability of CQ due to impaired de novo nucleotide biosynthesis and find that combination treatment with CQ and a replication stress response inhibitor is synthetically lethal in pancreatic cancer.Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancer-associated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors.