Abstract 7213: Targeting XPO1 to enhance the durability of response of MRTX1133 in pancreatic ductal adenocarcinoma

Abstract Introduction: The KRASG12D inhibitor MRTX1133, which targets KRAS in the OFF-state, is currently under evaluation in pancreatic ductal adenocarcinoma (PDAC) patients. However, as seen with other OFF-state KRAS inhibitors, MRTX1133 may provide only limited improvements in disease-free survival due to the emergence of drug resistance. This highlights the need for strategies to enhance the efficacy of KRAS inhibitors in PDAC. The nuclear transport protein, XPO1, plays a significant role in several pro-tumorigenic pathways and has been identified as a therapeutic vulnerability in KRAS-mutant cancers. It is overexpressed in many cancers, including PDAC, and its inhibition causes robust synthetic lethal interaction with oncogenic KRAS, indicating that targeting both XPO1 and KRAS may be beneficial. In this study, using several preclinical PDAC models, we have demonstrated that the second generation XPO1 inhibitor KPT8602 synergizes with and enhances the efficacy of MRTX1133. Methods: We generated KRASG12D inhibitor-resistant PDAC cells and assessed the effect of KPT8602 on their survival. We further tested different combinations of MRTX1133 and KPT8602 for their antiproliferative effects in 2D and 3D in vitro PDAC models. To test the in vivo antitumor efficacy of the combination, we used KRASG12D-mutant human PDAC cell-derived xenograft (CDX) and murine PDAC transgenic KPC cell-derived allograft models. Results: KPT8602 sensitized MRTX1133-resistant PDAC cells to growth inhibition, establishing that KRASG12D inhibitor-resistant cancer cells can potentially respond to KPT8602. Furthermore, treating multiple PDAC cell lines in 2D and 3D cultures with KPT8602 and MRTX1133 at different dose combinations resulted in synergistic inhibition of their viability. At the molecular level, the combination downregulated p-ERK, mTOR, p-4EBP1, DUSP6 and cyclin D1 expression in PDAC cells. Kinome analysis revealed reduced kinase activity for several kinases related to MAPK signaling in the combination treated PDAC cell lysates. Combining subtherapeutic doses of KPT8602 (15 mg/Kg BIW) and MRTX1133 (30 mg/Kg QD) caused significant tumor growth inhibition in multiple subcutaneous and orthotopic PDAC mouse models (p<0.001). Also, the combination treatment resulted in significantly enhanced survival in an immunocompetent orthotopic PDAC allograft model (p<0.001). Moreover, we have also demonstrated that maintenance with KPT8602 in combination treated mice prevented tumor relapse and resulted in a durable antitumor response in a PDAC CDX model. Conclusion: This is the first study showing that KPT8602 treatment can overcome resistance to MRTX1133 and synergistically augment the antitumor effects of MRTX1133 in PDAC preclinical models. This combination regimen can potentially prevent or delay drug resistance by making it feasible to achieve a more durable response at a lower dose of KRASG12D inhibitor. Citation Format: Husain Yar Khan, Amro Aboukameel, Sahar F. Bannoura, Md Hafiz Uddin, Fulya Koksalar Alkan, Ahmet B. Caglayan, Hilmi K. Alkan, Bin Bao, Hugo Jimenez, Mohammed Najeeb Al Hallak, Khalil Choucair, Steve Kim, Rafic Beydoun, Gregory Dyson, Yang Shi, Misako Nagasaka, Azeddine Atfi, Hasan Korkaya, Muhammad Wasif Saif, Philip A. Philip, Bassel El-Rayes, Anthony F. Shields, Ramzi M. Mohammad, Boris C. Pasche, Asfar S. Azmi. Targeting XPO1 to enhance the durability of response of MRTX1133 in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7213.