Abstract 3861: c-MYC mediated resistance to trametinib plus hydroxychloroquine in pancreatic cancer is overcome by CDK4/6 and lysosomal inhibition

Abstract Pharmacological inhibition of KRAS>RAF>MEK>ERK signaling has provided no clinical benefit to patients with pancreatic ductal adenocarcinoma (PDA). Interestingly, combined inhibition of MEK1/2 (with trametinib, T) plus autophagy (with chloroquine, CQ, or hydroxychloroquine, HCQ) demonstrated striking anti-tumor effects in preclinical models and in a patient (Patient 1). However, not all patients respond to the T/HCQ regimen, and Patient 1 eventually developed resistant disease. Here we report that primary or acquired resistance is associated with focal DNA copy number gains encompassing c-MYC. Furthermore, ectopic expression of c-MYC in PDA cell lines rendered them T/HCQ resistant. Interestingly, a CDK4/6 inhibitor, palbociclib (P), also induced autophagy and overrode c-MYC-mediated T/HCQ resistance, such that P/HCQ promoted regression of T/HCQ resistant PDA tumors with elevated c-MYC expression. Finally, P/HCQ treatment of Patient 1 resulted in a biochemical disease response. These data suggest that elevated c-MYC expression is both a marker and a mediator of T/HCQ resistance, which may be overcome by the use of palbociclib plus hydroxychloroquine. Citation Format: Mark Silvis, Dilru Silva, Rohweder Riley, Sophia Schuman, Swapna Gudipaty, Amanda Truong, Jeffery Yap, Kajsa Affolter, Martin McMahon, Conan Kinsey. c-MYC mediated resistance to trametinib plus hydroxychloroquine in pancreatic cancer is overcome by CDK4/6 and lysosomal inhibition. [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 3861.