Cyclin E1 and RTK/RAS signaling drive CDK inhibitor resistance via activation of E2F and ETS

// Barbie Taylor-Harding 1 , Paul-Joseph Aspuria 1 , Hasmik Agadjanian 1 , Dong-Joo Cheon 1 , Takako Mizuno 1, 2 , Danielle Greenberg 1 , Jenieke R. Allen 1, 2 , Lindsay Spurka 3 , Vincent Funari 3 , Elizabeth Spiteri 4 , Qiang Wang 1, 5 , Sandra Orsulic 1 , Christine Walsh 1, 6 , Beth Y. Karlan 1, 6 , W. Ruprecht Wiedemeyer 1 1 Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA 2 Graduate Program in Biomedical Sciences and Translational Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA 3 Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA 4 Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA 5 Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA 6 Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, CA 90048, USA Correspondence to: W. Ruprecht Wiedemeyer, e-mail: wiedemeyerw@cshs.org Keywords: Cyclin-dependent kinase inhibitors, palbociclib, dinaciclib, Cyclin E1, ovarian cancer Received: July 15, 2014      Accepted: November 02, 2014      Published: December 22, 2014 ABSTRACT High-grade serous ovarian cancers (HGSOC) are genomically complex, heterogeneous cancers with a high mortality rate, due to acquired chemoresistance and lack of targeted therapy options. Cyclin-dependent kinase inhibitors (CDKi) target the retinoblastoma (RB) signaling network, and have been successfully incorporated into treatment regimens for breast and other cancers. Here, we have compared mechanisms of response and resistance to three CDKi that target either CDK4/6 or CDK2 and abrogate E2F target gene expression. We identify CCNE1 gain and RB1 loss as mechanisms of resistance to CDK4/6 inhibition, whereas receptor tyrosine kinase (RTK) and RAS signaling is associated with CDK2 inhibitor resistance. Mechanistically, we show that ETS factors are mediators of RTK/RAS signaling that cooperate with E2F in cell cycle progression. Consequently, CDK2 inhibition sensitizes cyclin E1-driven but not RAS-driven ovarian cancer cells to platinum-based chemotherapy. In summary, this study outlines a rational approach for incorporating CDKi into treatment regimens for HGSOC.