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.
Highlights
A hallmark of cancer is unchecked cell division
To further characterize the selectivity of ribociclib and compare it to the selectivity of the cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors palbociclib and abemaciclib, the affinities of these molecules for CDK4 ± cyclin D1/D3 and 465 other kinases and disease-relevant mutant variants were analyzed using the KINOMEscan® selectivity screening platform (Supplementary Table 1A-1C). This analysis indicated that ribociclib and palbociclib have similar affinities for CDK4, which were ~10-fold lower than that observed for abemaciclib (Supplementary Table 1A)
All 3 molecules dissociated cyclin D–bound CDK4 from the capture matrix by >99% at these concentrations. These data show that ribociclib and palbociclib are highly selective for CDK4 relative to other kinases, whereas abemaciclib is more promiscuous, even when accounting for differences in affinity for CDK4
Summary
A hallmark of cancer is unchecked cell division. The product of RB1 is one such protein guarding the entry into S phase. In its quiescent (nonphosphorylated) state, retinoblastoma protein (Rb) binds to the E2 transcription factor (E2F) family members creating a transcriptional repression complex that is sufficient to arrest cells in G1 [2, 3, 5,6,7]. The D cyclins bind to and activate cyclin-dependent kinases 4 and 6 (CDK4/6), www.oncotarget.com which in turn phosphorylate Rb and leads to the release of E2F proteins [2, 3, 6] and derepression of E2F-dependent promotors [7]. Released E2F proteins activate genes required for S phase entry and DNA replication [6]
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