Mutation in CDC42 Gene Set as a Response Biomarker for Immune Checkpoint Inhibitor Therapy
ABSTRACT Background Immune checkpoint inhibitors (ICIs) have achieved great success; however, a subset of patients exhibits no response. Consequently, there is a critical need for reliable predictive biomarkers. Our focus is on CDC42, which stimulates multiple signaling pathways promoting tumor grow...
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| Format: | Article |
| Language: | English |
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Wiley
2025-01-01
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| Series: | Cancer Medicine |
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| Online Access: | https://doi.org/10.1002/cam4.70556 |
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| author | Kun Wang Yingying Zhang Zhaoming Su Bei Wang Yuanyang Zhou Xiaochu Tong Chengying Xie Xiaomin Luo Sulin Zhang Mingyue Zheng |
| author_facet | Kun Wang Yingying Zhang Zhaoming Su Bei Wang Yuanyang Zhou Xiaochu Tong Chengying Xie Xiaomin Luo Sulin Zhang Mingyue Zheng |
| author_sort | Kun Wang |
| collection | DOAJ |
| description | ABSTRACT Background Immune checkpoint inhibitors (ICIs) have achieved great success; however, a subset of patients exhibits no response. Consequently, there is a critical need for reliable predictive biomarkers. Our focus is on CDC42, which stimulates multiple signaling pathways promoting tumor growth. We hypothesize that an impaired function of CDC42 may serve as an indicator of a patient's response to ICI therapy. Methods We consider CDC42 and its downstream binding and effector proteins as a gene set, as mutations in these components could lead to defective CDC42 function. To elucidate the biomarker function of mutations within the CDC42 gene set, we curated a comprehensive discovery dataset that included seven ICI treatment cohorts. And we curated two ICI treatment cohorts for validation. We explored the mechanism based on The Cancer Genome Atlas database. We also examined whether combining a CDC42 inhibitor with ICI could enhance ICI's efficacy. Results Mutations in the CDC42 gene set were associated with improved overall survival and progression‐free survival. Furthermore, our analysis of immune response landscapes among different statuses of the CDC42 gene set supports its role as a biomarker. Animal experiments also revealed that the combination of the CDC42 inhibitor (ML141) with anti‐PD‐1 blockade can additively reduce tumor growth. Conclusions Our study suggests that the CDC42 gene set mutations could potentially serve as a novel biomarker for the clinical response to ICI treatment. This finding also provides insights into the potential of combining ICI and CDC42 inhibitor use for more efficient patient treatment. |
| format | Article |
| id | doaj-art-6c58d05b9e1a4ca39ac68787561b54bf |
| institution | Kabale University |
| issn | 2045-7634 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj-art-6c58d05b9e1a4ca39ac68787561b54bf2025-01-13T13:22:39ZengWileyCancer Medicine2045-76342025-01-01141n/an/a10.1002/cam4.70556Mutation in CDC42 Gene Set as a Response Biomarker for Immune Checkpoint Inhibitor TherapyKun Wang0Yingying Zhang1Zhaoming Su2Bei Wang3Yuanyang Zhou4Xiaochu Tong5Chengying Xie6Xiaomin Luo7Sulin Zhang8Mingyue Zheng9School of Life Sciences, Division of Life Sciences and Medicine University of Science and Technology of China Hefei ChinaSchool of Life Sciences, Division of Life Sciences and Medicine University of Science and Technology of China Hefei ChinaSchool of Chinese Materia Medica, Nanjing University of Chinese Medicine Nanjing ChinaSchool of Chinese Materia Medica, Nanjing University of Chinese Medicine Nanjing ChinaDrug Discovery and Design Center, State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai ChinaDrug Discovery and Design Center, State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai ChinaDrug Discovery and Design Center, State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai ChinaDrug Discovery and Design Center, State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai ChinaDrug Discovery and Design Center, State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai ChinaSchool of Life Sciences, Division of Life Sciences and Medicine University of Science and Technology of China Hefei ChinaABSTRACT Background Immune checkpoint inhibitors (ICIs) have achieved great success; however, a subset of patients exhibits no response. Consequently, there is a critical need for reliable predictive biomarkers. Our focus is on CDC42, which stimulates multiple signaling pathways promoting tumor growth. We hypothesize that an impaired function of CDC42 may serve as an indicator of a patient's response to ICI therapy. Methods We consider CDC42 and its downstream binding and effector proteins as a gene set, as mutations in these components could lead to defective CDC42 function. To elucidate the biomarker function of mutations within the CDC42 gene set, we curated a comprehensive discovery dataset that included seven ICI treatment cohorts. And we curated two ICI treatment cohorts for validation. We explored the mechanism based on The Cancer Genome Atlas database. We also examined whether combining a CDC42 inhibitor with ICI could enhance ICI's efficacy. Results Mutations in the CDC42 gene set were associated with improved overall survival and progression‐free survival. Furthermore, our analysis of immune response landscapes among different statuses of the CDC42 gene set supports its role as a biomarker. Animal experiments also revealed that the combination of the CDC42 inhibitor (ML141) with anti‐PD‐1 blockade can additively reduce tumor growth. Conclusions Our study suggests that the CDC42 gene set mutations could potentially serve as a novel biomarker for the clinical response to ICI treatment. This finding also provides insights into the potential of combining ICI and CDC42 inhibitor use for more efficient patient treatment.https://doi.org/10.1002/cam4.70556biomarkerCDC42clinical responseimmunotherapypan‐cancer |
| spellingShingle | Kun Wang Yingying Zhang Zhaoming Su Bei Wang Yuanyang Zhou Xiaochu Tong Chengying Xie Xiaomin Luo Sulin Zhang Mingyue Zheng Mutation in CDC42 Gene Set as a Response Biomarker for Immune Checkpoint Inhibitor Therapy Cancer Medicine biomarker CDC42 clinical response immunotherapy pan‐cancer |
| title | Mutation in CDC42 Gene Set as a Response Biomarker for Immune Checkpoint Inhibitor Therapy |
| title_full | Mutation in CDC42 Gene Set as a Response Biomarker for Immune Checkpoint Inhibitor Therapy |
| title_fullStr | Mutation in CDC42 Gene Set as a Response Biomarker for Immune Checkpoint Inhibitor Therapy |
| title_full_unstemmed | Mutation in CDC42 Gene Set as a Response Biomarker for Immune Checkpoint Inhibitor Therapy |
| title_short | Mutation in CDC42 Gene Set as a Response Biomarker for Immune Checkpoint Inhibitor Therapy |
| title_sort | mutation in cdc42 gene set as a response biomarker for immune checkpoint inhibitor therapy |
| topic | biomarker CDC42 clinical response immunotherapy pan‐cancer |
| url | https://doi.org/10.1002/cam4.70556 |
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