MCC Gene Silencing Is a CpG Island Methylator Phenotype-Associated Factor That Predisposes Colon Cancer Cells to Irinotecan and Olaparib

Abstract

Chemotherapy 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.

Molecular subtyping in colorectal cancer: A bridge to personalized therapy (Review)

“…Iacopetta et al (91) reported contrasting findings that patients with CIMP-positive CRC can benefit from 5-FU treatment, mainly related to the association between CIMP positivity and intracellular folic acid metabolism, and gene silencing caused by DNA methylation. A recent study claimed that CIMP-positive tumors are potentially more responsive to the topoisomerase-inhibitor, irinotecan (92). Although CIMP has been reported as a potential prognostic biomarker for drug decision-making, overall research on treating CIMP-positive tumors with hypomethylating drugs appears to be limited.…”