Dependency of Cholangiocarcinoma on Cyclin D-Dependent Kinase Activity

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 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 pRB is required for the activity of the CDK4/6 inhibitor and that loss of pRB conferred the CDK4/6 inhibitor-drug resistance. We also identified that the sensitivity of CCA to CDK4/6 inhibition is associated with the activated KRAS signature. The effectiveness of CDK4/6 inhibition for CCA was confirmed in the 3D spheroid, xenograft, and patient-derived xenograft models. Lastly, we identified a list of genes whose expressions can be used to predict the response to the CDK4/6 inhibitor. CONCLUSION: We uncovered 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 article is protected by copyright. All rights reserved.

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