Abstract PO-031: Lysosome inhibition overcomes resistance to CDK4/6 inhibition in PDA

Abstract

Abstract The current FDA-approved chemotherapies for patients with Pancreatic Ductal Adenocarcinoma (PDA) demonstrate substantial toxicities with only a modest survival benefit highlighting the urgent need to better understand the molecular mechanisms driving PDA and how they interact in order to develop more precise and less toxic pathway-targeted therapies. PDA often harbors oncogenic mutations in KRAS and CDKN2A that drive a dysregulated cell cycle through activation of CDK4/6 (Cyclin-Dependent Kinases 4 and 6), which mono-phosphorylate RB1 to govern progression through G0◊G1◊S phases. Currently, there are three FDA-approved CDK4/6 inhibitors, palbo-, abema-, and ribociclib (X-ciclibs), that are predicted to have anti-cancer activity in PDA cells. However, the benefits of X-ciclib treatment in PDA patients are largely underwhelming. We found that inherent resistance to X-ciclib treatment in vitro is due to compensatory activation of protective autophagy, a critical lysosomal degradation process that generates a source of nutrients during periods of cellular stress. We observed that X-ciclib treatment induces autophagic flux in PDA cell lines. This pro-cancer process can be targeted with the lysosomal inhibitors, chloroquine and hydroxychloroquine. The addition of chloroquine sensitizes PDA cells to X-ciclib treatment, resulting in diminished proliferative ability. Additionally, a late-stage PDA patient was treated with the combination of an X-ciclib and hydroxychloroquine and displayed a dramatic decrease in the bloodborne PDA biomarker, Cancer Antigen 19-9. These data may suggest a novel combination treatment strategy for late-stage PDA patients, but the molecular mechanisms underlying are yet to be studied in PDA. Future work will explore the role RB1 plays in CDK4/6 regulated autophagy by investigating how phosphorylation at distinct RB1 sites modulates autophagy-related gene expression and the extent to which mTORC1 deactivation is necessary for CDK4/6 regulated autophagy. Citation Format: Dilru Silva, Conan Kinsey, Martin McMahon. Lysosome inhibition overcomes resistance to CDK4/6 inhibition in PDA [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-031.