Publication: Dependency of Cholangiocarcinoma on Cyclin D–Dependent Kinase Activity
Issued Date
2019-11-01
Resource Type
ISSN
15273350
02709139
02709139
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2-s2.0-85068469861
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Mahidol University
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SCOPUS
Bibliographic Citation
Hepatology. Vol.70, No.5 (2019), 1614-1630
Suggested Citation
Gunya Sittithumcharee, Orawan Suppramote, Kulthida Vaeteewoottacharn, Chumphon Sirisuksakun, Supawan Jamnongsong, Phatthamon Laphanuwat, Monthira Suntiparpluacha, Arriya Matha, Porncheera Chusorn, Pongsakorn Buraphat, Chumpot Kakanaporn, Komgrid Charngkaew, Atit Silsirivanit, Krittiya Korphaisarn, Somchai Limsrichamrern, Pinpat Tripatara, Chawalit Pairojkul, Sopit Wongkham, Somponnat Sampattavanich, Seiji Okada, Siwanon Jirawatnotai Dependency of Cholangiocarcinoma on Cyclin D–Dependent Kinase Activity. Hepatology. Vol.70, No.5 (2019), 1614-1630. doi:10.1002/hep.30704 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/51340
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Title
Dependency of Cholangiocarcinoma on Cyclin D–Dependent Kinase Activity
Author(s)
Gunya Sittithumcharee
Orawan Suppramote
Kulthida Vaeteewoottacharn
Chumphon Sirisuksakun
Supawan Jamnongsong
Phatthamon Laphanuwat
Monthira Suntiparpluacha
Arriya Matha
Porncheera Chusorn
Pongsakorn Buraphat
Chumpot Kakanaporn
Komgrid Charngkaew
Atit Silsirivanit
Krittiya Korphaisarn
Somchai Limsrichamrern
Pinpat Tripatara
Chawalit Pairojkul
Sopit Wongkham
Somponnat Sampattavanich
Seiji Okada
Siwanon Jirawatnotai
Orawan Suppramote
Kulthida Vaeteewoottacharn
Chumphon Sirisuksakun
Supawan Jamnongsong
Phatthamon Laphanuwat
Monthira Suntiparpluacha
Arriya Matha
Porncheera Chusorn
Pongsakorn Buraphat
Chumpot Kakanaporn
Komgrid Charngkaew
Atit Silsirivanit
Krittiya Korphaisarn
Somchai Limsrichamrern
Pinpat Tripatara
Chawalit Pairojkul
Sopit Wongkham
Somponnat Sampattavanich
Seiji Okada
Siwanon Jirawatnotai
Abstract
© 2019 by the American Association for the Study of Liver Diseases. 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.