XPO1 inhibition as a clinically viable strategy to enhance durability of response to KRAS ^G12D inhibitor in pancreatic ductal adenocarcinoma.

736 Background: The OFF State (GDP bound) KRASG 12D inhibitor MRTX1133 is currently being evaluated in pancreatic ductal adenocarcinoma (PDAC) patients. Nevertheless, as with other OFF state KRAS G12C inhibitors sotorasib and adagrasib, the KRAS G12D inhibitor may yield only a modest increase in disease-free survival due to emergence of drug resistance. This underscores the need to identify strategies that can enhance the efficacy of KRAS inhibitors in PDAC. Nuclear protein transport plays an important role in several pro-tumorigenic pathways and has been shown to be a therapeutic vulnerability in KRAS mutant cancers. XPO1 is the major nuclear exporter and plays a pivotal role in shuttling various critical tumor suppressors, genome surveillance proteins, and transcription factors out of the nucleus and is frequently overexpressed in various cancers, including PDAC. In this study, we employed a KRAS G12D inhibitor resistant model and evaluated its sensitivity to nuclear exporter protein inhibitor. Methods: We examined the cytotoxic and molecular effects of KRAS G12D inhibitor MRTX1133 in combination with nuclear transport inhibitor eltanexor in KRAS G12D inhibitor resistant models. The preclinical antitumor efficacy of the combination was evaluated in KRAS G12D mutant PDAC cell derived xenograft (CDX) subcutaneous and orthotopic models. Results: Eltanexor treatment reversed MRTX1133 resistance in vitro yielding suppressed proliferation of KRAS G12D mutant 2D and 3D cultures of PDAC cell lines and patient derived primary tumors cells. High throughput P-kinome analysis showed suppression of a larger repertoire of MAPK substrates in combination treatment compared to single agent group. Eltanexor and MRTX1133 combination led to reduction in protein expression of KRAS downstream effectors and cell cycle markers. Furthermore, a combined administration of eltanexor and MRTX1133 at sub-optimal doses resulted in remarkable tumor growth inhibition in multiple subcutaneous and orthotopic KRAS G12D mutant mice models. Moreover, eltanexor as a maintenance therapy also prevented tumor relapse indicating durability of response in PDAC. Conclusions: This is the first study demonstrating that nuclear transport inhibitors can overcome KRAS G12D inhibitor MRTX1133 resistance in PDAC cells. This study provides a rationale for combining MRTX1133 with eltanexor for the treatment of PDAC patients with KRAS G12D mutant tumors.