Mutation in CDC42 Gene Set as a Response Biomarker for Immune Checkpoint Inhibitor Therapy
Kun Wang1,2,3, Yingying Zhang1,2,3, Zhaoming Su4
1School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
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.
Insights
Mutations in the CDC42 gene set may predict patient response to immune checkpoint inhibitors (ICIs). This finding could lead to better patient selection and combination therapies for improved cancer treatment outcomes.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Immune checkpoint inhibitors (ICIs) show promise but lack predictive biomarkers for non-responders.
- CDC42 signaling pathways are implicated in tumor growth, suggesting a role in treatment response.
Purpose of the Study:
- To investigate CDC42 gene set mutations as predictive biomarkers for ICI therapy response.
- To explore the mechanistic basis and therapeutic potential of targeting CDC42 in conjunction with ICIs.
Main Methods:
- Analysis of a comprehensive discovery dataset (seven ICI cohorts) and validation dataset (two ICI cohorts) for CDC42 gene set mutations.
- Exploration of The Cancer Genome Atlas (TCGA) database for mechanistic insights.
- Evaluation of combining a CDC42 inhibitor with ICI in preclinical models.
Main Results:
- CDC42 gene set mutations correlated with improved overall survival and progression-free survival in ICI-treated patients.
- Immune response landscape analysis supported the role of the CDC42 gene set as a predictive biomarker.
- Combination therapy with a CDC42 inhibitor (ML141) and anti-PD-1 blockade demonstrated additive tumor growth reduction in vivo.
Conclusions:
- Mutations within the CDC42 gene set represent a potential novel biomarker for predicting clinical response to ICI therapy.
- Targeting CDC42 in combination with ICIs may offer a more effective therapeutic strategy for cancer patients.
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