Reference Detail

Ref Type

Journal Article

PMID

(24919854)

Authors

Gelbert LM, Cai S, Lin X, Sanchez-Martinez C, Del Prado M, Lallena MJ, Torres R, Ajamie RT, Wishart GN, Flack RS, Neubauer BL, Young J, Chan EM, Iversen P, Cronier D, Kreklau E, de Dios A

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Investigational new drugs	32	5	2014 Oct	825-37	Invest New Drugs

URL

Abstract Text

The 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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Abemaciclib	Abemaciclib	4	59

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Abemaciclib	Verzenio	LY2835219	CDK4/6 Inhibitor 13	Verzenio (abemaciclib) is a dual CDK4/6 inhibitor, which inhibits Rb1 protein phosphorylation and may induce cell cycle arrest and prevent growth in cancer cells (PMID: 24919854). Verzenio (abemaciclib) is FDA approved as a monotherapy and in combination with Faslodex (fulvestrant) in patients with hormone receptor-positive, ERBB2 (HER2) receptor-negative advanced or metastatic breast cancer, in combination with endocrine therapy as adjuvant treatment for patients with hormone receptor-positive, ERBB2 (HER2) receptor-negative, node-positive, early breast cancer at high risk of recurrence, and in combination with an aromatase inhibitor as initial therapy for patients with hormone receptor-positive, ERBB2 (HER2) receptor-negative advanced or metastatic breast cancer (FDA.gov).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References