Jahan , ZeenatBenthani, FahadCurrey , NicolaParker, Hannah W.Dahlstrom, JaneCaldon , C. ElizabethKohonen-Corish, Maija R J2024-10-282024-10-282072-6694https://hdl.handle.net/1885/733721992Chemotherapy is a mainstay of colorectal cancer treatment, and often involves a combination drug regime. CpG island methylator phenotype (CIMP)-positive tumors are potentially more responsive to the topoisomerase-inhibitor irinotecan. The mechanistic basis of the increased sensitivity of CIMP cancers to irinotecan is poorly understood. Mutated in Colorectal Cancer (MCC) is emerging as a multifunctional tumor suppressor gene in colorectal and liver cancers, and has been implicated in drug responsiveness. Here, we found that CIMP tumors undergo MCC loss almost exclusively via promoter hypermethylation rather than copy number variation or mutations. A subset of cancers display hypomethylation which is also associated with low MCC expression, particularly in rectal cancer, where CIMP is rare. MCC knockdown or deletion was found to sensitize cells to SN38 (the active metabolite of irinotecan) or the PARP-inhibitor Olaparib. A synergistic effect on cell death was evident when these drugs were used concurrently. The improved SN38/irinotecan efficacy was accompanied by the down-regulation of DNA repair genes. Thus, differential methylation of MCC is potentially a valuable biomarker to identify colorectal cancers suitable for irinotecan therapy, possibly in combination with PARP inhibitors.This work was supported by grants from the Cancer Council NSW (RG17-05, RG19-01), Gastroenterological Society of Australia (2017), Sydney Catalyst (FB) and Australian Government Research Training Program Scholarships to Fahad Benthani and Hannah Parker. Elizabeth Caldon was supported by a Cancer Institute NSW Fellowship (2020/CDF1071application/pdfen-AU© 2022 The authorshttp://creativecommons.org/licenses/by/4.0/colorectal cancerprecision medicineepigenetic biomarkermutated in colorectal cancer (MCC)CIMP202210.3390/cancers141228592024-02-11Creative Commons Attribution licence