Dependency of Cholangiocarcinoma on Cyclin D – Dependent Kinase Activity.

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Siriraj Excellent Center for Systems Pharmacology, Faculty of Medicine, Siriraj Hospital, Mahidol University

Project Title:

Roles of Cyclin D1 Oncogenic Network in Tumorigenesis and Cancer Targeted Therapy.

Research Title:

Dependency of Cholangiocarcinoma on Cyclin D – Dependent Kinase Activity.

Researcher (s):

Gunya Sittithumcharee (Mahidol University), Orawan Suppramote (Mahidol University), Kulthida Vaeteewoottacharn (Khon Kaen University), Sirisuksakun Chumpon (Mahidol University), Supawan Jamnongsong (Mahidol University), Phatthamon Laphanuwat (Mahidol University), Monthira Suntiparpluacha (Mahidol University), Areeya Matha (Mahidol University), Porncheera Chusorn (Mahidol University), Pongsakorn Buraphat (Mahidol University), Chumpot Kakanaporn (Mahidol University), Komgrid Charngkaew (Mahidol University), Atit Silsirivanit (Khon Kaen University), Kritiya Korphaisarn (Mahidol University), Somchai Limsrichamrern (Mahidol University), Pinpat Tripatara (Mahidol University), Chaowalit Tripatara (Khon Kaen University), Sopit Wongkham (Khon Kaen University), Somponnat Sampattavanich (Mahidol University), Seiji Okada (Kumamoto University), Siwanon Jirawatnotai (Mahidol University)

Cholangiocarcinoma (CCA) is a bile duct cancer with a very poor prognosis. Currently, there is no effective pharmacological treatment available for it. We showed that CCA ubiquitously relies on cyclin-dependent kinases 4 and 6 (CDK4/6) activity to proliferate. Primary CCA tissues express high levels of cyclin D1 and the specific marker of CDK4/6 activity, phospho-RB Ser780. Treatment of a 15-CCA cell line collection by pharmacological CDK4/6 inhibitors leads to reduced numbers of cells in the S-phase and senescence in most of the CCA cell lines. We found that expression of retinoblastoma protein (pRB) is required for activity of the CDK4/6 inhibitor, and that loss of pRB conferred CDK4/6 inhibitor-drug resistance. We also identified that sensitivity of CCA to CDK4/6 inhibition is associated with the activated KRAS signature. Effectiveness of CDK4/6 inhibition for CCA was confirmed in the three-dimensional spheroid-, xenograft-, and patient-derived xenograft models. Last, we identified a list of genes whose expressions can be used to predict response to the CDK4/6 inhibitor. Conclusion: We investigated a ubiquitous dependency of CCA on CDK4/6 activity and the universal response to CDK4/6 inhibition. We propose that the CDK4/6-pRB pathway is a suitable therapeutic target for CCA treatment. This work has been accepted for a publication in a top-rated scientific journal in the field, HEPATOLOGY (impact factor 14.1). This work paved down a fundamental for the investigator-initiated clinical trial for CCA, and attracted attention of the pharma and research community to the cancer research capability in Thailand which will eventually promote Thailand into the global research value chain.

Full paper can be found at: Hepatology. 11 May 2019., doi: 10.1002/hep.30704. Dependency of Cholangiocarcinoma on Cyclin D – Dependent Kinase Activity.