Abstract 5313: A BCL-XL PROTAC degrader DT2216 synergizes with KRASG12C inhibitors for effectively treating KRASG12C-mutated cancers

Abstract Purpose: Mutations in KRAS are the most common oncogenic drivers. Sotorasib (AMG510), a covalent inhibitor selectively targeting KRASG12C, was recently approved for the treatment of KRASG12C-mutated non-small cell lung cancer (NSCLC). However, the clinical efficacy of sotorasib and other KRASG12C inhibitors is limited by intrinsic resistance in colorectal cancer (CRC) and by the rapid emergence of acquired resistance in all treated solid tumors. Therefore, there is an urgent need to develop novel combination therapies to overcome sotorasib resistance and to maximize its efficacy. Experimental Design: A panel of KRASG12C-mutated cell lines from NSCLC, CRC and pancreatic cancer (PC) were treated with sotorasib alone or in combination with BCL-XL proteolysis targeting chimera (PROTAC, such as DT2216) to assess effects on cell viability, colony formation and apoptosis. To identify mechanisms underlying sotorasib+DT2216 combination responses, we analyzed KRAS downstream signaling and expression of BCL-2 family proteins, and performed co-immunoprecipitation of BCL-XL to evaluate its interaction with pro-apoptotic BH3-only proteins. Finally, therapeutic efficacy of sotorasib alone and in combination with DT2216 was evaluated in vivo using different tumor xenograft models. Results: We observed heterogeneous responses to sotorasib alone, whereas its combination with DT2216 strongly inhibited viability of KRASG12C cell lines that partially responded to sotorasib treatment. Mechanistically, co-treatment with DT2216 inhibited sotorasib-induced BCL-XL/BIM interaction leading to enhanced apoptosis. Furthermore, DT2216 co-treatment significantly improved the antitumor efficacy of sotorasib in vivo. Conclusions: Our findings suggest that due to cytostatic activity, the efficacy of sotorasib is limited, and therefore its combination with a pro-apoptotic agent DT2216 shows synergistic responses and can potentially overcome resistance. Citation Format: Sajid Khan, Janet Wiegand, Peiyi Zhang, Wanyi Hu, Dinesh Thummuri, Vivekananda Budamagunta, Nan Hua, Lingtao Jin, Carmen J. Allegra, Edmund S. Kopetz, Maria Zajac-Kaye, Frederic J. Kaye, Guangrong Zheng, Daohong Zhou. A BCL-XL PROTAC degrader DT2216 synergizes with KRASG12C inhibitors for effectively treating KRASG12C-mutated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5313.