The potent and selective cyclin-dependent kinases 4 and 6 inhibitor ribociclib (LEE011) is a versatile combination partner in preclinical cancer models

// Sunkyu Kim 1 , Ralph Tiedt 2 , Alice Loo 1 , Thomas Horn 1 , Scott Delach 1 , Steven Kovats 1 , Kristy Haas 1 , Barbara Schacher Engstler 2 , Alexander Cao 1 , Maria Pinzon-Ortiz 1 , Iain Mulford 1 , Michael G. Acker 1 , Rajiv Chopra 3 , Christopher Brain 4 , Emmanuelle di Tomaso 1 , William R. Sellers 1 and Giordano Caponigro 1 1 Novartis Institutes for BioMedical Research, Oncology Disease Area, Cambridge, MA, USA 2 Novartis Institutes for BioMedical Research, Oncology Disease Area, Basel, Switzerland, USA 3 Novartis Institutes for BioMedical Research, Chemical Biology & Therapeutics, Cambridge, MA, USA 4 Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Cambridge, MA, USA Correspondence to: Giordano Caponigro, email: giordano.caponigro@novartis.com Keywords: CDK4/6 inhibitor; ribociclib; LEE011; preclinical; selectivity Received: May 22, 2018     Accepted: September 15, 2018     Published: October 16, 2018 ABSTRACT Inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) is associated with robust antitumor activity. Ribociclib (LEE011) is an orally bioavailable CDK4/6 inhibitor that is approved for the treatment of hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer, in combination with an aromatase inhibitor, and is currently being evaluated in several additional trials. Here, we report the preclinical profile of ribociclib. When tested across a large panel of kinase active site binding assays, ribociclib and palbociclib were highly selective for CDK4, while abemaciclib showed affinity to several other kinases. Both ribociclib and abemaciclib showed slightly higher potency in CDK4 -dependent cells than in CDK6 -dependent cells, while palbociclib did not show such a difference. Profiling CDK4/6 inhibitors in large-scale cancer cell line screens in vitro confirmed that RB1 loss of function is a negative predictor of sensitivity. We also found that routinely used cellular viability assays measuring adenosine triphosphate levels as a proxy for cell numbers underestimated the effects of CDK4/6 inhibition, which contrasts with assays that assess cell number more directly. Robust antitumor efficacy and combination benefit was detected when ribociclib was added to encorafenib, nazartinib, or endocrine therapies in patient-derived xenografts.