CRISPR-Cas9 screening identifies KRAS-induced COX-2 as a driver of immunotherapy resistance in lung cancer.
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Date
2024-04-18ICR Author
Author
Boumelha, J
de Castro, A
Bah, N
Cha, H
de Carné Trécesson, S
Rana, S
Tomaschko, M
Anastasiou, P
Mugarza, E
Moore, C
Goldstone, R
East, P
Litchfield, K
Lee, S-H
Molina-Arcas, M
Downward, J
Type
Journal Article
Metadata
Show full item recordAbstract
Oncogenic KRAS impairs anti-tumor immune responses. As effective strategies to combine KRAS inhibitors and immunotherapies have so far proven elusive, a better understanding of how 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 cyclooxygenase-2 (COX-2) in cancer cells. Oncogenic KRAS potently induced COX-2 in both mouse and human lung cancer, which was suppressed using KRAS inhibitors. COX-2 acted via prostaglandin E2 (PGE2) to promote resistance to immune checkpoint blockade (ICB) in lung adenocarcinoma. Targeting COX-2/PGE2 remodeled the tumor microenvironment by inducing pro-inflammatory polarization of myeloid cells and influx of activated cytotoxic CD8+ T cells, which increased the efficacy of ICB. Restoration of COX-2 expression contributed to tumor relapse after prolonged KRAS inhibition. These results provide the rationale for testing COX-2/PGE2 pathway inhibitors in combination with KRASG12C inhibition or ICB in patients with KRAS-mutant lung cancer.
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Research team
Lung Cancer Group
Language
eng
Date accepted
2024-04-08
License start date
2024-04-18
Citation
Cancer Research, 2024,
Publisher
American Association for Cancer Research (AACR)