BCL-X_L PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRAS^G12C-mutated cancers.

ABSTRACT: KRAS mutations are the most common oncogenic drivers. Sotorasib (AMG510), a covalent inhibitor of KRAS^G12C, was recently approved for the treatment of KRAS^G12C-mutated non-small cell lung cancer (NSCLC). However, the efficacy of sotorasib and other KRAS^G12C inhibitors is limited by intrinsic resistance in colorectal cancer (CRC) and by the rapid emergence of acquired resistance in all treated tumors. Therefore, there is an urgent need to develop novel combination therapies to overcome sotorasib resistance and to maximize its efficacy. We assessed the effect of sotorasib alone or in combination with DT2216 (a clinical-stage BCL-X_L proteolysis targeting chimera [PROTAC]) on KRAS^G12C-mutated NSCLC, CRC and pancreatic cancer (PC) cell line

SUBMITTER: Khan S 

PROVIDER: S-EPMC8905794 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature