Asfar S. Azmi

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, in part due to the high prevalence of activating KRAS mutations, particularly KRASG12D. The selective KRASG12D inhibitor MRTX1133 is currently in clinical development and represents a significant advance for PDAC therapy. However, like other OFF-state KRAS inhibitors, MRTX1133 shows limited long-term benefit due to acquired drug resistance. This has created an urgent need for rational combination strategies that not only boost initial efficacy but also extend therapeutic durability.

Nuclear export protein XPO1 is a well-characterized oncogenic facilitator that regulates nuclear-cytoplasmic trafficking of tumor suppressors and key transcription factors. XPO1 is frequently overexpressed in PDAC, and its inhibition creates synthetic lethality in KRAS-driven cancers. Our hypothesis was that co-inhibition of XPO1 and KRASG12D could resensitize resistant tumors and promote sustained responses.

In this study, we utilized MRTX1133-resistant PDAC cell lines and evaluated the efficacy of the second-generation XPO1 inhibitor KPT8602 (eltanexor). The combination demonstrated potent synergy in both 2D and 3D cultures and showed robust tumor regression in multiple in vivo models, including immunocompetent KPC allografts. Mechanistically, the combination treatment significantly downregulated MAPK signaling components (p-ERK, mTOR, p-4EBP1), cell cycle regulators, and kinome-wide MAPK pathway activity. Importantly, the addition of KPT8602 as a maintenance therapy prevented tumor relapse in CDX models, highlighting the potential for durable disease control.

This presentation will share new preclinical evidence supporting XPO1 inhibition as a clinically actionable strategy to improve KRASG12D-targeted therapy in PDAC and outlines a translational framework for advancing this combination into clinical trials.