Dual effects of DLG5 (disks large homolog 5 gene) modulation on chemotherapy‐induced thrombocytopenia and nausea/vomiting via the hippo signalling pathway

Abstract Background and Purpose The CAPEOX (combination of oxaliplatin and capecitabine) chemotherapy protocol is widely used for colorectal cancer treatment, but it can lead to chemotherapy‐induced adverse effects (CRAEs). Experimental Approach To uncover the mechanisms and potential biomarkers for CRAE susceptibility, we performed whole‐genome sequencing on normal colorectal tissue (CRT) before adjuvant chemotherapy. This is followed by in vivo and in vitro verifications for selected gene and CRAE pair. Key Results Our analysis revealed specific germline mutations linked to Grade 2 (or higher) chemotherapy‐induced thrombocytopenia (CIT) and nausea/vomiting (CINV). Notably, both CRAEs were associated with mutations in the DLG5 gene. We found that DLG5 mutations related to CIT were associated with increased gene expression, while those associated with CINV were linked to suppressed gene expression, as indicated by the Genotype‐Tissue Expression (GTEX) database. In megakaryocytes, overexpression of human DLG5 suppressed the hippo signalling pathway and induced YAP expression. In zebrafish, overexpression of human DLG5 not only reduced platelet production but also inhibited thrombus formation. Subsequent qPCR analysis revealed that DLG5 overexpression affected genes involved in cytoskeleton formation and alpha‐granule formation, which could impact the normal generation of proplatelets. Conclusion and Implications We identified a series of germline mutations associated with susceptibility to CIT and CINV. Of particular interest, we demonstrated that induced and suppressed DLG5 expression is respectively related to CIT and CINV. These findings shed light on the involvement of the hippo signalling pathway and DLG5 in the development of CRAEs, providing valuable insights into potential targets for therapeutic interventions.