Abstract A056: Targeting the mevalonate biosynthesis pathway in gemcitabine resistant pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a low survival rate. A lack of durable responses to chemotherapy renders its treatment particularly challenging and largely contributes to the devastating prognosis. Gemcitabine, a pyrimidine anti-metabolite, is a cornerstone in PDA therapy, but resistance remains a major hurdle in clinical care. Multiple mechanisms of chemoresistance have been attributed to rewired metabolic pathways in PDA cells. Accordingly, we hypothesized that altered metabolism in gemcitabine resistance represents a therapeutic vulnerability that can be targeted to improve response to treatment. To investigate metabolic vulnerabilities in gemcitabine resistance, we generated gemcitabine resistant murine PDA cell lines and assembled patient-derived gemcitabine high versus low responder organoids. Transcriptomic profiling revealed a downregulation of the mevalonate biosynthesis pathway and its rate-limiting enzyme, HMG-CoA reductase, upon the acquisition of gemcitabine resistance. Upregulation of this pathway has been proposed as a primary resistance mechanism to statins, HMG-CoA reductase inhibitors that are frequently prescribed to treat patients with hyperlipidemia. Accordingly, we postulated that statins would be more potent in gemcitabine resistant PDA cells than in their sensitive counterparts. Indeed, resistant cells were exquisitely susceptible to inhibition of the mevalonate pathway, an observation consistent across multiple clinically available statins. Downstream rescue experiments suggested that the main impact of blocking the mevalonate biosynthesis pathway is through lowered levels of geranylgeranyl pyrophosphate and reduced protein geranylation. To validate our findings in vivo, we implanted gemcitabine resistant murine PDA cells into syngeneic mice that were fed with a modified diet precluding geranylgeraniol. Here, the treatment combination gemcitabine and pitavastatin inhibited tumor growth of resistant allografts. Collectively, these data suggest that targeting the HMG-CoA reductase is a metabolic vulnerability that is gained in PDA cells upon the acquisition of gemcitabine resistance. The combination therapy gemcitabine and pitavastatin, two widely used compounds in patients, has potential to translate into a clinical benefit and improve survival in this deadly disease. Citation Format: Alica K. Beutel, Sabrina Calderon, Ethan Nghiem, Rima Singh, Cecily Anaraki, Kevin Gulay, Herve Tiriac, Alexander Kleger, Thomas Seufferlein, Alexander Muir, Cholsoon Jang, Dennis Juarez, David Fruman, Christopher Halbrook. Targeting the mevalonate biosynthesis pathway in gemcitabine resistant pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A056.