CRISPR-Cas9 Screening Identifies KRAS-Induced COX2 as a Driver of Immunotherapy Resistance in Lung Cancer.

ABSTRACT: Oncogenic KRAS impairs antitumor immune responses. As effective strategies to combine KRAS inhibitors and immunotherapies have so far proven elusive, a better understanding of the mechanisms by which oncogenic KRAS drives immune evasion is needed to identify approaches that could sensitize KRAS-mutant lung cancer to immunotherapy. In vivo CRISPR-Cas9 screening in an immunogenic murine lung cancer model identified mechanisms by which oncogenic KRAS promotes immune evasion, most notably via upregulation of immunosuppressive COX2 in cancer cells. Oncogenic KRAS potently induced COX2 in both mouse and human lung cancer, which was suppressed using KRAS inhibitors. COX2 acted via prostaglandin E2 (PGE2) to promote resistance to immune checkpoint blockade (ICB) in lung adenocarcinoma. Targeting C

SUBMITTER: Boumelha J 

PROVIDER: S-EPMC11247323 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature