Abstract C086: Investigating resistance to RAS therapies in PDAC models

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) carries a significantly unfavorable prognosis due to delayed detection and limited therapeutic options, resulting in high mortality rates. The majority of PDAC tumors (>90%) harbor activating mutations in the KRAS oncogene, making KRAS an attractive target for investigating the complex biology of PDAC and identifying potential genetic vulnerabilities that can be exploited for patient treatment. Although small molecules targeting Kras have shown promising results in preclinical and clinical studies of PDAC, the responses have not been durable, and understanding the mechanisms of resistance is a current challenge for the field. To overcome these challenges, we employed two genetic models to mimic Kras inhibition by small molecules. Firstly, using the FPC mouse model, we deleted an endogenous oncogenic KrasG12V allele in mice with measurable PDAC. Secondly, we utilized Auxin-inducible degron 2 (mAID-Auxin) technology to induce acute degradation of Kras proteins, enabling us to evaluate the efficacy of Kras degradation both in vitro and in vivo. Both models led to acute tumor regressions followed by eventual relapse, providing another approach for modeling response and resistance. Acute Kras degradation resulted in a rapid decrease in p-ERK signaling and tumor cell proliferation and alterations in multiple signaling pathways. Sustained degradation of KrasG12D resulted in tumor relapse that predominantly exhibited a mesenchymal phenotype. Intriguingly, we observed several epithelial foci within the relapsed tumors, which displayed reactivated p-ERK signaling. In summary, our study presents an acute ablation model of oncogenic Kras in PDAC, effectively recapitulating the response observed in Kras inhibition both in vitro and in vivo. Furthermore, our model provides insights into the survival mechanism following Kras loss and the mechanisms underlying tumor relapse upon long-term Kras inhibition in PDAC. These findings contribute to our understanding of PDAC biology and offer potential avenues for alternative therapeutic interventions. Citation Format: Hsiu-Chi Ting, Sun Kim, Youngkyu Park, Astrid Deschnes, Jonathan Kastan, Jeremy Nigri, David Tuveson. Investigating resistance to RAS therapies in PDAC models [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 C086.