Genomic Aberrations that Activate D-type Cyclins Are Associated with Enhanced Sensitivity to the CDK4 and CDK6 Inhibitor Abemaciclib

Publication date: 11 December 2017
Source:Cancer Cell, Volume 32, Issue 6
Author(s): Xueqian Gong, Lacey M. Litchfield, Yue Webster, Li-Chun Chio, Swee Seong Wong, Trent R. Stewart, Michele Dowless, Jack Dempsey, Yi Zeng, Raquel Torres, Karsten Boehnke, Cecilia Mur, Carlos Marugán, Carmen Baquero, Chunping Yu, Steven M. Bray, Isabella H. Wulur, Chen Bi, Shaoyou Chu, Hui-Rong Qian, Philip W. Iversen, Farhana F. Merzoug, Xiang S. Ye, Christoph Reinhard, Alfonso De Dios, Jian Du, Charles W. Caldwell, María José Lallena, Richard P. Beckmann, Sean G. Buchanan
Most cancers preserve functional retinoblastoma (Rb) and may, therefore, respond to inhibition of D-cyclin-dependent Rb kinases, CDK4 and CDK6. To date, CDK4/6 inhibitors have shown promising clinical activity in breast cancer and lymphomas, but it is not clear which additional Rb-positive cancers might benefit from these agents. No systematic survey to compare relative sensitivities across tumor types and define molecular determinants of response has been described. We report a subset of cancers highly sensitive to CDK4/6 inhibition and characterized by various genomic aberrations known to elevate D-cyclin levels and describe a recurrent CCND1 3′UTR mutation associated with increased expression in endometrial cancer. The results suggest multiple additional classes of cancer that may benefit from CDK4/6-inhibiting drugs such as abemaciclib.

Teaser

Gong et al. identify a subset of cancers highly sensitive to CDK4/6 inhibition, which are characterized by various genomic aberrations known to elevate D-cyclin levels but not by CDKN2A mutations. They also identify a recurrent CCND1 3′UTR mutation associated with increased CCND1 expression in endometrial cancer.


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