Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in KRASG12C-mutant Colorectal Cancer.

ABSTRACT: Novel covalent inhibitors of KRASG12C have shown limited response rates in patients with KRASG12C-mutant (MT) colorectal cancer. Thus, novel KRASG12C inhibitor combination strategies that can achieve deep and durable responses are needed. Small-molecule KRASG12C inhibitors AZ'1569 and AZ'8037 were used. To identify novel candidate combination strategies for AZ'1569, we performed RNA sequencing, siRNA, and high-throughput drug screening. Top hits were validated in a panel of KRASG12CMT colorectal cancer cells and in vivo. AZ'1569-resistant colorectal cancer cells were generated and characterized. We found that response to AZ'1569 was heterogeneous across the KRASG12CMT models. AZ'1569 was ineffective at inducing apoptosis when used as a single agent or combined with chemotherapy or agents t

SUBMITTER: Khawaja H 

PROVIDER: S-EPMC9808374 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature