ML-792

Cholangiocarcinoma (CCA) includes a diverse group of biliary malignancies with poor prognosis. Alterations in post-translational modifications contribute to disrupted protein dynamics, cellular disturbances, and disease. This study investigates the role of protein SUMOylation in cholangiocarcinogenesis and its potential as a therapeutic target.

Analysis of CCA tumors from 4 patient cohorts and CCA cell lines, revealed increased expression of the SUMOylation machinery genes SUMO activating enzyme 1 ( SAE1 ) and the SUMO conjugating enzyme UBE2I , regardless of the tumor’s molecular profile, resulting in elevated levels of SUMO1-conjugated proteins. Higher SAE1 and UBE2I levels were both indicative of unfavorable clinical outcomes. Deregulated SUMOylated proteins in CCA, mostly linked to cell proliferation, survival, and homeostasis, were identified through immunoprecipitation and mass spectrometry. Genetic ( UBE2I -knockdown) and pharmacological (ML792 and S-adenosyl-methionine) inhibition of SUMOylation effectively suppressed tumorigenesis in subcutaneous and oncogene-driven CCA models, reducing the presence of cancer-associated fibroblasts and increasing the recruitment of antitumor immune cells. In vitro, targeting SUMOylation induced CCA cell death and reduced cell proliferation, colony formation, and spheroid growth. Importantly, ML792 and S-adenosyl-methionine did not adversely affect normal human cholangiocytes. Moreover, co-culture of wild-type or UBE2I -knockdown CCA cells with cancer-associated fibroblasts revealed that depleting SUMOylation in CCA cells impaired cancer-associated fibroblast cell growth and altered their protein secretome, ultimately disrupting CCA growth through a regulatory feedback loop.

Aberrant SUMOylation drives CCA progression by enhancing cell survival, proliferation, and shaping the tumor microenvironment. Targeting SUMOylation shows potential in inhibiting CCA growth, representing a promising therapeutic strategy.

Cells overexpressing MYC depend on SUMOylation for survival and cell division. To assess the therapeutic potential of SUMO inhibition, we screened 30 patient-derived ovarian cancer models (OCMs) with the SUMO-activating enzyme inhibitor ML-792. While most were resistant, seven displayed intermediate sensitivity, and a further five were particularly sensitive, with sensitivity accompanied by mitotic errors, polyploidy, apoptosis, and PML body expansion. Resistance was linked to ABCB1 upregulation, and inhibiting drug efflux sensitized eight resistant OCMs. MYC target genes were enriched in sensitive models, consistent with MYC being a potential driver of response. SUMO inhibition induced an adaptive transcriptional response in resistant cells, but this was attenuated in MYC-overexpressing cells, raising the possibility that transcriptional interference disrupts the homeostatic controls required to buffer the inhibition of SUMO signaling. SUMO sensitivity did not overlap with PARP inhibitor sensitivity, supporting the therapeutic potential of apex SUMO inhibitors to target a subset of homologous-recombination-proficient ovarian cancers.