Abstract B077: KRASG12D inhibitor MRTX1133 synergizes with the next generation nuclear transport protein inhibitor eltanexor resulting in enhanced antitumor activity against pancreatic ductal adenocarcinoma
Authors: Khan Husain Y. , Aboukameel Amro , Uddin Md Hafiz , Al-Hallak Mohammad Najeeb , Beal Eliza W. , Azar Ibrahim , Baloglu Erkan , Beydoun Rafic , Sukari Ammar , Nagasaka Misako , Mohamed Amr , Kaseb Ahmed , Philip Philip A. , El-Rayes Basel , Chen Herbert , Shields Anthony , Azmi Asfar 
Published: January 2024

Abstract
Introduction: The novel KRAS inhibitor MRTX1133 that targets the G12D isoform, a major KRAS mutation in pancreatic ductal adenocarcinoma (PDAC) patients, has been recently developed and expected to benefit a large PDAC patient population. However, based on clinical outcomes of sotorasib (KRASG12C inhibitor) in the lung cancer setting, it is likely that the KRASG12D inhibitor will also show modest increase in disease-free survival in PDAC patients because of emergence of drug resistance. Hence, there is a pressing need to identify strategies to enhance the efficacy of KRAS inhibitors in PDAC. There is evidence that nuclear transport protein exportin 1 (XPO1) is a druggable vulnerability in KRAS mutant cancers. XPO1 guides the movement of several key tumor suppressors, genome surveillance proteins and transcription factors out of the nucleus and is known to be overexpressed in many cancers including PDAC. In this study, using in vitro and in vivo models, we have tested eltanexor/KPT-8602 (an investigational, next generation selective inhibitor of XPO1) for its ability to synergize with the KRASG12D inhibitor and to sensitize KRASG12D inhibitor resistant PDAC cells. Methods: We examined the cytotoxicity and molecular profile of KRASG12D inhibitor MRTX1133 in combination with XPO1 inhibitor KPT-8602 in KRASG12D mutant 2D and 3D cellular/spheroid models. The antitumor activity of the combination was further evaluated in a KRASG12D mutant cell line-derived xenograft model. Results: KPT-8602 synergized with MRTX1133 yielding suppressed growth of KRASG12D mutant PDAC cells, but not in KRASwt, KRASG12V, and KRASG12C cell lines (NCI RASless MEFs). Similar synergistic effects were also seen in 3D culture models where the combination synergistically enhanced the disintegration of PDAC spheroids. In addition, the combination reduced the clonogenic potential of KRASG12D mutant PDAC cells. Furthermore, we developed a PDAC cell line resistant to MRTX1133 and observed that such MRTX1133-resistant cell line was acutely sensitive to treatment with KPT-8602. Moreover, KPT-8602 and MRTX1133 combination resulted in enhanced inhibition of KRAS downstream effector pathways. In xenograft studies, oral administration of KPT-8602 and intraperitoneal administration of MRTX1133 at sub-optimal doses demonstrated remarkable suppression of KRASG12D mutant HPAC tumor burden in ICR-SCID mice. Conclusion: This is the first study showing that XPO1 inhibitor KPT-8602 can synergize with KRASG12D inhibitor MRTX1133. This combination can simultaneously target direct KRAS downstream effectors and the nuclear transport machinery warranting further clinical investigations.
Citation Format: Husain Y. Khan, Amro Aboukameel, Md Hafiz Uddin, Mohammad Najeeb Al-Hallak, Eliza W. Beal, Ibrahim Azar, Erkan Baloglu, Rafic Beydoun, Ammar Sukari, Misako Nagasaka, Amr Mohamed, Ahmed Kaseb, Philip A. Philip, Basel El-Rayes, Herbert Chen, Anthony Shields, Asfar Azmi. KRASG12D inhibitor MRTX1133 synergizes with the next generation nuclear transport protein inhibitor eltanexor resulting in enhanced antitumor activity against pancreatic ductal adenocarcinoma [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 B077.