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Although oncogenic Kirsten rat sarcoma virus (KRAS) was once deemed undruggable, recent advances have revealed promising anti-tumor effects with pan-KRAS and KRAS-mutant specific inhibitors in both preclinical and clinical settings. Despite the success of these inhibitors, the diversity of tumors as well as tumor sensitivity results in acquired drug resistance suggesting that combinational therapeutic approaches would be necessary to avoid this problem. An attractive combination strategy would be to couple KRAS inhibition with a blockade of its guanine exchange factor, Son of Sevenless (SOS1). This would keep KRAS in its inactive state as well as mitigate upstream MAPK pathway reactivation notoriously associated with inhibition in this pathway. Utilizing our PRODEGY platform, we developed bifunctional SOS1 degraders for the treatment of patients with KRAS mutant cancers. These degraders have shown rapid and potent CRBN-mediated degradation which exhibit DC50s 90% degradation of SOS1 in tumors and subsequently led to significant tumor growth inhibition as a single agent. Combination treatment of the KRAS G12C inhibitor AMG510 and SOS1 degraders produced strong synergistic antiproliferative effects in H358 and MIA PaCa-2 cell lines. Additionally, synergy was observed with SOS1 degraders and the EGFR inhibitor, Erlotinib, as well as the MEK inhibitor, Trametinib, in KRAS G13D mutant LoVo cells. The ability of our SOS1 degraders to have potency alone as well as in combination with multiple types of different RTK/RAS/MAPK pathway inhibitor highlights the value of SOS1 degraders as a potential therapeutic option for a range of KRAS mutant cancers. Citation Format: Kyle Begovich, Angela Schoolmeesters, Navin Rajapakse, Maneesh Kumar, Elena Martinez-Terroba, Arvind Shakya, Brandon Whitefield, Nataraj Pagadala, Aparajita Chourasia, Leah Fung. Development of bifunctional CRBN-SOS1 degraders for treatment of mutant KRAS cancers [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr B002. |
