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.