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Verzenio ® (abemaciclib) tablets
50mg, 100mg, 150mg, 200mg
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What is the mechanism of action of VERZENIO® (abemaciclib)?
Verzenio (abemaciclib) is an inhibitor of CDK4 and CDK6 and with continuous exposure resulted in senescence and apoptosis.
What is the mechanism of action of VERZENIO® (abemaciclib)?
Indication
Abemaciclib is indicated
- in combination with endocrine therapy (ET) (tamoxifen or an aromatase inhibitor [AI]) for the adjuvant treatment of adult patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), node-positive, early breast cancer at high risk of recurrence,
- in combination with an AI as initial endocrine-based therapy for the treatment of adult patients with HR+, HER2- advanced or metastatic breast cancer (MBC),
- in combination with fulvestrant for the treatment of adult patients with HR+, HER2- advanced or MBC with disease progression following ET, and
- as monotherapy for the treatment of adult patients with HR+, HER2- advanced or MBC with disease progression following ET and prior chemotherapy in the metastatic setting.1
Mechanism of Action
Abemaciclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and CDK6. These kinases are activated upon binding to D-cyclins. In estrogen receptor-positive breast cancer cell lines, cyclin D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation. In vitro, continuous exposure to abemaciclib inhibited Rb phosphorylation and blocked progression from G1 into S phase of the cell cycle, resulting in senescence and apoptosis. In breast cancer xenograft models, abemaciclib dosed daily without interruption as a single agent or in combination with antiestrogens resulted in reduction of tumor size.1
Preclinical Activity
Abemaciclib inhibits CDK 4 and CDK6 activity with marked specificity over other CDKs (eg, CDK1, CDK2, CDK5, and CDK7) in vitro and induces G1 arrest and apoptosis in Rb-proficient cells.2,3
Abemaciclib inhibits CDK4 and CDK6 at half maximal inhibitory concentration (IC50) of 2 nM and 10 nM, respectively.4-7
In cell-free biochemical assays, abemaciclib potently inhibited the kinase activity of both CDK4 and CDK6 when complexed with cyclin D family members. There was a 14-fold higher potency for inhibiting CDK4/cyclinD1 (CCND1) (0.6 nmol/L) as compared to CDK6/cyclinD3 (CCND3) (8.2 nmol/L).2,3Further analysis conducted with in-vitro cell-based assays confirmed preferential CDK4 inhibition.8,9
Preclinical results have demonstrated that a chronic or continuous dosing strategy is important for achieving durable cell-cycle arrest.4
Prolonged and continuous abemaciclib treatment led to sustained antitumor effects through inhibition of cell proliferation, altered cell metabolism, and triggered senescence and apoptosis. Treatment with abemaciclib resulted in significant inhibition of expression of genes involved in cell cycle regulation including Ki67 and longer treatment was associated with a loss of replicative capacity in breast cancer cells.3,8
Related Video
An animation of the mechanism of action of abemaciclib is available here: Abemaciclib Mechanism of Action.
Enclosed Prescribing Information
References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1Verzenio [package insert]. Indianapolis, IN: Eli Lilly and Company; 2023.
2Gelbert LM, Cai S, Lin X, et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014;32(5):825-837. http://dx.doi.org/10.1007/s10637-014-0120-7
3Torres-Guzmán R, Calsina B, Hermoso A, et al. Preclinical characterization of abemaciclib in hormone receptor positive breast cancer. Oncotarget. 2017;8(41):69493-69507. https://doi.org/10.18632/oncotarget.17778
4Tate SC, Cai S, Ajamie RT, et al. Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts. Clin Cancer Res. 2014;20(14):3763-3774. http://dx.doi.org/10.1158/1078-0432.CCR-13-2846
5Sanchez-Martinez C, Gelbert LM, Shannon H, et al. LY2835219, a potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6) that crosses the blood-brain barrier and demonstrates in vivo activity against intracranial human brain tumor xenografts. Mol Cancer Ther. 2011;10(11 suppl):B234. AACR-NCI-EORTC International Conference abstract B234. http://dx.doi.org/10.1158/1535-7163.targ-11-b234
6Dempsey JA, Chan EM, Burke TF, Beckmann RP. LY2835219, a selective inhibitor of CDK4 and CDK6, inhibits growth in preclinical models of human cancer. Cancer Res. 2013;73(8 suppl):LB-122. American Association for Cancer Research abstract LB-122. https://dx.doi.org/10.1158/1538-7445.AM2013-LB-122
7Patnaik A, Rosen LS, Tolaney SM, et al. Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer. Poster presented at: 105th Annual Meeting of the American Association for Cancer Research (AACR); April 5-9, 2014; San Diego, CA. Accessed March 22, 2022. http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3404&sKey=eae7ac93-fe0a-452f-a725-84c120b59aaf&cKey=63bf641a-bbc5-41a8-86ca-cd984d9d199a&mKey=6ffe1446-a164-476a-92e7-c26446874d93
8Torres-Guzmán R, Ganado MP, Mur C, et al. Continuous treatment with abemaciclib leads to sustained and efficient inhibition of breast cancer cell proliferation. Oncotarget. 2022;13:864-875. https://doi.org/10.18632/oncotarget.28249
9Wander SA, O'Brien N, Litchfield LM, et al. Targeting CDK4 and 6 in cancer therapy: emerging preclinical insights related to abemaciclib. Oncologist. Published online August 2, 2022. https://doi.org/10.1093/oncolo/oyac138
Date of Last Review: October 11, 2024