Dr. Richard Finn on the Rationale for Targeting CDK4/6

Richard Finn, MD, Division of Hematology/Oncology at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles, discusses the rationale for targeting cyclin-dependent kinases (CDK) 4 and 6 with the novel agent PD 0332991 in breast cancer.

The CDK4/6 proteins play an important role in regulating cell cycle progression, Finn notes. Preclinical models showed preferential activity in ER-positive breast cancer, including those with HER2-amplification. In both the preclinical and clinical models, the tumor's sensitivity to PD 0332991 was indicated by the presence of an intact retinoblastoma (RB) pathway, which is common in ER-positive tumors. Mechanistically, the inhibition of CDK4/6 prevents the deactivation of the RB tumor suppressor protein.

Following the preclinical work, a phase II study examined PD 0332991 plus letrozole as a treatment for postmenopausal women with ER-positive metastatic breast cancer. The addition of letrozole, a nonsteroidal aromatase inhibitor, was based on preclinical evidence of synergy between PD 0332991 and antiestrogen agents. Overall, the combination of these agents in the phase II trial resulted in an 18.6-month improvement in progression-free survival.