CDK10 in Gastrointestinal Cancers: Dual Roles as a Tumor Suppressor and Oncogene

Abstract

Cyclin-dependent kinase 10 (CDK10) is a CDC2-related serine/threonine kinase involved in cellular processes including cell proliferation, transcription regulation and cell cycle regulation. CDK10 has been identified as both a candidate tumor suppressor in hepatocellular carcinoma, biliary tract cancers and gastric cancer, and a candidate oncogene in colorectal cancer (CRC). CDK10 has been shown to be specifically involved in modulating cancer cell proliferation, motility and chemosensitivity. Specifically, in CRC, it may represent a viable biomarker and target for chemoresistance. The development of therapeutics targeting CDK10 has been hindered by lack a specific small molecule inhibitor for CDK10 kinase activity, due to a lack of a high throughput screening assay. Recently, a novel CDK10 kinase activity assay has been developed, which will aid in the development of small molecule inhibitors targeting CDK10 activity. Discovery of a small molecular inhibitor for CDK10 would facilitate further exploration of its biological functions and affirm its candidacy as a therapeutic target, specifically for CRC.

Keywords: CDK10; biliary tract cancer; colorectal cancer; cyclin-dependent kinases; gastric cancer; gastrointestinal cancers; hepatocellular carcinoma.

Figure 1

CDK10 isoforms and interacting partners. (A) Protein sequence alignment of the full length CDK10 isoform (blue) and the splice variant (yellow). (B) Schematics of the full length CDK10 isoform and splice isoform, showing the ATP binding domain, the Ser/Thr kinase domain and Thr133, which is involved in Pin1 binding. (C) Models of CDK10 full-length protein and splice isoform with putative binding partners. Figures were created using BioRender. (D) Proposed CDK10 oncogenic signaling pathways. (E) Proposed CDK10 tumor suppressive signaling pathways. “?” denotes not yet shown in gastrointestinal and hepatobiliary cancers (, –64).