60P - Mechanism of action for combined CDK4/6 and ER inhibition in ER positive breast cancer
|Date||08 May 2014|
|Session||Welcome reception and Poster Walk|
|Topics|| Breast Cancer
|Citation||Annals of Oncology (2014) 25 (suppl_1): i21-i22. 10.1093/annonc/mdu069|
M. Koehler1, T.L. VanArsdale2, D. Shields3, K. Arndt4, J. Yuan2, N. Lee2, K. Eisele2, J. Chionis2, J. Cao2, C.L. Painter2
Disruption of the Retinoblastoma tumor suppressor is observed with substantial frequency in virtually every type of cancer where it has been examined. Occurring through direct genetic loss or mutation of RB1 or deregulation of the molecular pathway in which RB1 functions. Tumors retaining intact RB1 functions rely on the activity of CyclinD-CDK4/6 complexes to inactivate RB1 and promote progression through the G1 restriction point into S phase. Hormone receptor positive breast cancers are one tumor type where RB1 remains intact in most tumors and deregulation of CDK4/6-Cyclin D signaling is common. As such, dependence on CDK4/6 signaling in ER positive breast cancers has been demonstrated using the specific CDK4/6 inhibitor PD-0332991 (Palbociclib), and the combination of Palbociclib and Letrozole has been shown to provide significant clinical activity in ER breast cancer patients. To determine the mechanism of action for this combination, we investigated the effects of Palbociclib with anti-estrogen therapeutics on ER breast cancer cell lines. Mechanistic analyses reveal that the combination of Palbociclib with fulvestrant or letrozole enhanced inhibition of Rb phosphorylation leading to significantly greater loss of E2F1, FoxM1 and downstream target genes such as PLK-1, SKP2 and CCNE2, leading to greater inhibition of cell proliferation. The enhanced growth arrest is accompanied by hallmarks of cell senescence, and the arrest of cells following drug removal is maintained for cells treated with the combination. To explore these activities in vivo an ER breast patient derived xenograft model was studied using the combination of Palbociclib and aromatase inhibitor Letrozole. These studies recapitulate in vitro model systems, showing greater tumor growth inhibition with combination therapy, enhanced dephosphorylation of RB1 and accompanied inhibition of downstream signaling. PDX tumors treated with the combination of Palbociclib and Letrozole displayed reduced KI67 staining compared to single agent treatments and b-galactosidase staining revealed that cell senescence is also a component of the functional response of ER breast tumors to the combined inhibition of CDK4/6 and ER signaling in vivo.
All authors have declared the following: Employee of Pfizer, Inc.