Abstract 4568: Rational targeting of BCL-xL and/or mTOR enhance the efficacy of KRASG12D inhibitor in pancreatic cancer

Abstract Background: Pancreatic cancer (PaCa) is a highly aggressive malignancy with a very low five-year survival rate secondary to late diagnosis, limited treatment options and resistance to existing therapies. While the emergence of mutant-selective KRASG12D (G12D) inhibitors brings promise for treating PaCa patients carrying these mutations, their effectiveness as single agents is expected to be limited as evident from the clinical efficacy of KRASG12C inhibitors. Experimental Design: First, multiple G12D-mutated PaCa cell lines were treated with a G12D inhibitor (MRTX1133) and subjected to immunoblot analysis for the expression of KRAS effectors and BCL-2 family proteins. Next, a proteolysis-targeting chimera (PROTAC) -based platelet-sparing BCL-xL degrader (DT2216) and/or an mTOR inhibitor (everolimus) were evaluated in combination with MRTX1133 for viability, clonogenicity and apoptosis. Subsequently, mechanistic investigations were carried out using immunoblotting, senescence-associated β-galactosidase staining and qPCR. Finally, therapeutic efficacy and safety of the combinations were evaluated in cell-derived and patient-derived xenograft models. Results: MRTX1133 treatment creates apoptotic vulnerabilities by inducing aberrations in BCL-2 family proteins, with elevated BIM levels and decreased NOXA levels, in G12D-mutated PaCa cells. Furthermore, DT2216 and everolimus were shown to release BIM and stabilize NOXA, respectively, and their combination with MRTX1133 synergistically killed G12D-mutated PaCa cells in vitro and caused significant tumor growth inhibition or regression compared to single agents in vivo. Additionally, MRTX1133 treatment led to induction of senescence in a fraction of PaCa cells. These senescent cells were found to be dependent on BCL-xL and MCL-1 for their survival and were effectively killed with a combination of DT2216 and everolimus through BCL-xL degradation and NOXA-mediated MCL-1 inhibition, respectively. Conclusions: Our findings suggest that the single agent efficacy of MRTX1133 is limited due to apoptosis inhibition and complimentary senescence induction, and therefore its combination with DT2216 and/or everolimus is synergistic, which can potentially overcome resistance, by enhanced apoptosis and clearance of senescent cells. Citation Format: Sajid Khan, Lin Cao, Vignesh Vudhata, Yang Yang, Peiyi Zhang, Guangrong Zheng, Jose G. Trevino, Daohong Zhou. Rational targeting of BCL-xL and/or mTOR enhance the efficacy of KRASG12D inhibitor in pancreatic cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4568.