Facts and Hopes on RAS Inhibitors and Cancer Immunotherapy.
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Date
2023-12-15ICR Author
Author
Boumelha, J
Molina-Arcas, M
Downward, J
Type
Journal Article
Metadata
Show full item recordAbstract
Although the past decade has seen great strides in the development of immunotherapies that reactivate the immune system against tumors, there have also been major advances in the discovery of drugs blocking oncogenic drivers of cancer growth. However, there has been very little progress in combining immunotherapies with drugs that target oncogenic driver pathways. Some of the most important oncogenes in human cancer encode RAS family proteins, although these have proven challenging to target. Recently drugs have been approved that inhibit a specific mutant form of KRAS: G12C. These have improved the treatment of patients with lung cancer harboring this mutation, but development of acquired drug resistance after initial responses has limited the impact on overall survival. Because of the immunosuppressive nature of the signaling network controlled by oncogenic KRAS, targeted KRAS G12C inhibition can indirectly affect antitumor immunity, and does so without compromising the critical role of normal RAS proteins in immune cells. This serves as a rationale for combination with immune checkpoint blockade, which can provide additional combinatorial therapeutic benefit in some preclinical cancer models. However, in clinical trials, combination of KRAS G12C inhibitors with PD-(L)1 blockade has yet to show improved outcome, in part due to treatment toxicities. A greater understanding of how oncogenic KRAS drives immune evasion and how mutant-specific KRAS inhibition impacts the tumor microenvironment can lead to novel approaches to combining RAS inhibition with immunotherapies.
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Research team
Lung Cancer Group
Language
eng
Date accepted
2023-08-01
License start date
2023-08-15
Citation
Clinical Cancer Research, 2023, pp. CCR-22-3655 -
Publisher
AMER ASSOC CANCER RESEARCH