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Targeting KRAS in colorectal cancer immunotherapy: rationale, challenges and future directions
Gongmin Zhu1, Lijiao Pei2, Di Ye1
1Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China.
Abstract:
Kirsten rat sarcoma (KRAS) is frequently mutated in colorectal cancer (CRC). In recent years, mutant KRAS has shed its "undruggable" label, with two clinically approved inhibitors now available. Besides aberrantly activating intrinsic tumor cell growth signaling, oncogenic KRAS contributes to the development of an immunosuppressive tumor microenvironment (TME), especially in CRC. This suggests KRAS inhibition may enhance responsiveness to immunotherapy, supporting the rationale for combining mutant KRAS inhibitors with immune checkpoint blockade (ICB). Mutant KRAS is considered as an ideal immunological target. Emerging therapeutics, including vaccines, TCR-T cell therapies and antibodies, are being developed to treat KRAS-mutant CRC patients that leverage peptides or peptide/major histocompatibility complex class I (MHC-I) complexes generated by mutant KRAS. Here, we provide an overview of targeting mutant KRAS in CRC immunotherapy, discussing challenges and future directions.
Insights
Targeting Kirsten rat sarcoma (KRAS) mutations in colorectal cancer (CRC) is evolving. Mutant KRAS inhibitors combined with immunotherapy show promise for treating CRC by overcoming tumor immunosuppression.
Area of Science:
- Oncology
- Immunology
- Cancer Therapeutics
Background:
- Kirsten rat sarcoma (KRAS) mutations are common in colorectal cancer (CRC).
- Mutant KRAS was previously considered undruggable, but inhibitors are now available.
- Oncogenic KRAS promotes tumor growth and an immunosuppressive tumor microenvironment (TME) in CRC.
Purpose of the Study:
- To provide an overview of targeting mutant KRAS in colorectal cancer (CRC) immunotherapy.
- To discuss the rationale for combining mutant KRAS inhibitors with immune checkpoint blockade (ICB).
- To explore emerging therapeutics for KRAS-mutant CRC.
Main Methods:
- Review of current literature on KRAS inhibition and immunotherapy in CRC.
- Discussion of challenges and future directions in targeting mutant KRAS.
- Overview of novel therapeutics including vaccines, TCR-T cell therapies, and antibodies.
Main Results:
- Mutant KRAS inhibitors are clinically available, addressing the 'undruggable' KRAS.
- KRAS inhibition may enhance immunotherapy response by counteracting TME-mediated immunosuppression.
- Emerging immunotherapies leverage mutant KRAS peptides or peptide/MHC-I complexes.
Conclusions:
- Mutant KRAS is a viable immunological target in CRC.
- Combining KRAS inhibitors with ICB is a promising strategy for CRC treatment.
- Further development of KRAS-targeted immunotherapies is crucial for improving patient outcomes.
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