Ditercalinium chloride: A potential inhibitor targeting recurrent in frame COMMD10-AP3S1 fusions in CRCs

Abstract

Recent research has shown that fusion genes are promising molecular targets for cancer treatment. However, investigations on fusion genes having biomarker potential and functionally implicated in CRCs are sorely missing. Our goal was to identify and characterize fusion genes having significant biomarker potential and functionally implicated in CRCs. We performed a comprehensive analysis using different databases and available literature related to fusion genes in CRCs. Our systematic analysis using defined criteria identified fusion genes significantly associated with CRCs. 40 fusion candidates were selected based on their frequency, expression status in normal and colorectal adenocarcinoma, fusion topography (loss/gain of the functional domain), and functional role in cancers. Our inclusion and exclusion criteria pinpointed 7 important fusion candidates (COMMD10-AP3S1, RAD51C-ATXN7, CAD-ALK, EML4-ALK, LMNA-NTRK1, TPM3-NTRK1, and EPCAM-MSH2) which may be playing a crucial role in colorectal carcinogenesis. Stagewise expression and overall survival analysis of 7 fusion genes and their partners suggested that COMMD10-AP3S1 was significantly associated with differential expression (p = 6.311E−05) and combined overall survival (p = 0.032) in CRCs, suggesting its biomarker potential. Further, sequence analysis revealed that COMMD10-AP3S1 was an in-frame fusion. Homology modeling of the in-frame COMMD10-AP3S1 and virtual screening of the ZINC 15 database (29,851 compounds) against the fusion protein suggested that ZINC000004215707 had the lowest binding energy of −12.7 kcal/mol. Homology modeling and virtual screening identified ditercalinium chloride (ZINC000004215707) as a potential ligand against the in-frame COMMD10-AP3S1 fusion protein that could serve as a choice of therapy with COMMD10-AP3S1 fusions in CRCs.