Mechanism of Action

First-in-class IBRANCE delivers dual inhibition with endocrine therapy by selectively inhibiting CDK4/6 downstream of ER

CDK4/6=cyclin-dependent kinases 4 and 6; ER=estrogen receptor.

Both CDK4 and CDK6 are key regulators of cell division1,2
  • Inhibition of CDK4/6 helps control cell growth by inducing G1 arrest and reducing cell-cycle progression
  • It is important to inhibit both CDK4 and CDK6 for effective suppression of tumor activity
CDK4/6 is also active in healthy cells3,4
  • Inhibiting CDK4/6 in healthy cells can result in side effects, some of which may be serious
  • Human bone marrow mononuclear cells treated with palbociclib in the presence or absence of an antiestrogen in vitro did not become senescent and resumed proliferation following palbociclib withdrawal. This evidence suggests IBRANCE may not have cytotoxic effects on bone marrow cells

THE PIONEERING CDK4/6 INHIBITOR

IBRANCE was the first therapy to bring the science of CDK4/6 inhibition into clinical practice

 

REFERENCES
1. Fry DW, Harvey PJ, Keller PR, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004;3(11):1427-1438.
2. Chen P, Lee NV, Hu W, et al. Spectrum and degree of CDK drug interactions predicts clinical performance. Mol Cancer Ther. 2016;15(10):2273-2281.
3. Prall OWJ, Sarcevic B, Musgrove EA, Watts CKW, Sutherland RL. Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. J Biol Chem. 1997;272(16):10882-10894.
4. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25-35.