Mutation in CDC42 gene set as a response biomarker for immune checkpoint inhibitor therapy

Background Immunotherapy has proven notably effective in treating tumors across diverse patient populations. However, some patients do not respond to immune checkpoint inhibitors (ICIs). Thus, there is a need for reliable biomarkers that can predict clinical responses to ICI treatment accurately. Methods Our focus is on CDC42, a protein that stimulates multiple signaling pathways, promoting tumor growth. We hypothesize that its defective function may indicate a patient's response to ICI therapy. We consider CDC42, along with its downstream binding and effector proteins, as a gene set. This is because their mutation could result in defective CDC42 function. We investigated the mutations in the CDC42 gene set as a potential biomarker for clinical benefits from ICI treatment. We also examined whether the combined use of a CDC42 inhibitor and ICI could enhance the efficacy of ICI. Results The presence of mutations in the CDC42 gene set correlated with improved overall survival (OS: p = 2.9E-4) and progression-free survival (PFS: p = 2.92E-6). Furthermore, our analysis of immune response landscapes among different CDC42 gene set statuses supports its potential as a biomarker for ICI therapy. Animal experiments also revealed that combining the CDC42 inhibitor (ML141) with anti-PD-1 blockade can synergistically reduce tumor growth. Conclusions Our study suggests that the CDC42 gene set could serve as a novel biomarker for the clinical response to ICI treatment. This finding also provides insight into the potential of combining ICI and CDC42 inhibitor use. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement We gratefully acknowledge financial support from National Natural Science Foundation of China (T2225002, 82273855 to M.Y.Z.), SIMM-SHUTCM Traditional Chinese Medicine Innovation Joint Research Program (E2G805H), Shanghai Municipal Science and Technology Major Project, National Key Research and Development Program of China (2022YFC3400504 to M.Y.Z.), the Youth Innovation Promotion Association CAS (2023296 to S.L.Z.) and the Natural Science Foundation of Shanghai (22ZR1474300 to S.L.Z.). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Immunotherapy treatment datasets were obtained from https://www.cbioportal.org and https://www.sciencedirect.com/science/article/pii/S0092867417311224?via%3Dihub TCGA datasets were obtained from https://portal.gdc.cancer.gov/ and https://www.sciencedirect.com/science/article/pii/S0092867418302290#mmc1 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript