Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine

Abstract

SummaryThe G1 restriction point is critical for regulating the cell cycle and is controlled by the Rb pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). This pathway is important because of its inactivation in a majority of human tumors. Transition through the restriction point requires phosphorylation of retinoblastoma protein (Rb) by CDK4/6, which are highly validated cancer drug targets. We present the identification and characterization of a potent CDK4/6 inhibitor, LY2835219. LY2835219 inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. In vivo target inhibition studies show LY2835219 is a potent inhibitor of Rb phosphorylation, induces a complete cell cycle arrest and suppresses expression of several Rb-E2F-regulated proteins 24 hours after a single dose. Oral administration of LY2835219 inhibits tumor growth in human tumor xenografts representing different histologies in tumor-bearing mice. LY2835219 is effective and well tolerated when administered up to 56 days in immunodeficient mice without significant loss of body weight or tumor outgrowth. In calu-6 xenografts, LY2835219 in combination with gemcitabine enhanced in vivo antitumor activity without a G1 cell cycle arrest, but was associated with a reduction of ribonucleotide reductase expression. These results suggest LY2835219 may be used alone or in combination with standard-of-care cytotoxic therapy. In summary, we have identified a potent, orally active small-molecule inhibitor of CDK4/6 that is active in xenograft tumors. LY2835219 is currently in clinical development.Electronic supplementary materialThe online version of this article (doi:10.1007/s10637-014-0120-7) contains supplementary material, which is available to authorized users.

The CDK4/6 Inhibitor LY2835219 Overcomes Vemurafenib Resistance Resulting from MAPK Reactivation and Cyclin D1 Upregulation

“…Using these in vitro and in vivo models, we show that cyclin D1 is generally elevated and functions as a critical node for the survival of vemurafenib-resistant cells. We further demonstrate that LY2835219, a selective dual CDK4/6 inhibitor currently in phase II clinic studies (29), can overcome vemurafenib resistance in these resistant models. Altogether, this study sheds new light on mechanisms of resistance to B-RAF inhibition, identifies cyclin D1 elevation concurrent with MAPK reactivation as a common resistant mechanism, and proposes targeting cyclin D1 through CDK4/6 inhibition by LY2835219 as an effective therapeutic strategy to overcome B-RAF resistance.…”

Targeting CDK6 in cancer: State of the art and new insights

“…Mechanistically, these drug candidates inhibit CDK4/6, halt Rb phosphorylation and arrest G1 cell cycle progression of cancer cells. 51,[90][91][92][93] PD0332991 has also demonstrated to cause almost identical senescence phenotypes as the endogenous CDK inhibitors p16 INK4a and p21 Cip1 do. 94 PD0332991 is a pyridopyrimidine derivative ( Table 2) developed by Pfizer with relative high level of selectivity toward CDK4 and CDK6.…”

“…It is currently in clinical trials for the treatment of stage IV non-small cell lung cancer and HR C /HER2 ¡ breast cancer. 92,107,108 In addition to the above clinical experimental drug compounds, a few pre-clinical CDK4/6 inhibitors, i.e., 7X, AMG925, Compound 6, Compound A and PD0183812, have been reported. [109][110][111][112][113] The chemical structures and CDK inhibitory activity of these compounds are summarized in Table 3.…”

Endocrine Therapeutic Strategies for Patients with Hormone Receptor-positive Advanced Breast Cancer

“…42 This compound has been investigated in combination with endocrine therapy, in two hazard ratio, 0.553; 95% CI, 0.449 to 0.681; p<0.001). 43 Unlike CDK4/6 inhibitors palbociclib and ribociclib, the most common adverse event in the abemaciclib arm was diarrhoea (86.4%), followed by neutropaenia (46.0%), nausea (45.1%) and fatigue (39.9%).…”