59O - Targeting CDK4/6 in Her2 positive breast cancer: Therapeutic effect, markers, and combination strategies

Date 08 May 2014
Event IMPAKT 2014
Session Best abstracts session
Topics Drug Development
Breast Cancer
Translational Research
Presenter Erik Knudsen
Citation Annals of Oncology (2014) 25 (suppl_1): i21-i22. 10.1093/annonc/mdu069
Authors E. Knudsen1, D. Cox2, J. Franco2, A. Frankel3, B. Haley4, A. Witkiewicz2
  • 1Pathology, University of Texas Southwestern, 75390 - Dallas/US
  • 2Pathology, University of Texas Southwestern Medical Center, 75390 - Dallas/US
  • 3Internal Medicine, University of Texas Southwestern Medical Center, 75390 - Dallas/US
  • 4Clinical Oncology, University of Texas Southwestern Medical Center, 75390 - Dallas/US

 

Abstract

Purpose:

In spite of the efficacy of Her2-targeted therapies, recurrence and progression remain a challenge for treatment of advanced Her2 positive breast cancer. CDK4/6 controls a key pathway downstream of Her2, hence inhibition of these kinases represents a therapeutic approach to augment the effectiveness of standard therapies.

Methods:

A combination of cell culture, mouse models, and human primary tumor explants were used to evaluate the therapeutic effect of the CDK4/6 inhibitor PD-0332991 as a single agent and to define markers of response. Parallel studies evaluated the mechanisms of action in combination with the Her2-targeted agents Lapatinib and T-DM1.

Results:

CDK4/6 inhibition resulted in profound cytostatic arrest, induction of senescence, and inhibition of invasive properties in Her2-positive cell culture models. These data were recapitulated with significant suppression of Ki67 in the MMTV-Her2 mouse model (p < 0.05) and Her2-positive xenografts (p < 0.01). Furthermore, in a series of more than 20 primary breast tumor explants, treatment with PD-0332991 resulted in a greater than 5-fold suppression of the Ki67 (p < 0.01). These effects of PD-0332991 were dependent on an intact RB-pathway, and consonantly, loss of RB and high-levels of p16 were associated with resistance to CDK4/6 inhibition. In models of acquired resistance to Her2-targeted therapies Cyclin D1 was inappropriately activated, and PD-0332991 treatment was effective at blocking proliferation by targeting this common pathway driving resistance. Combination studies carried out in cell lines and primary tumor explants illustrated that PD-0332991 provides a complementary mechanism of action to T-DM1, and efficiently suppresses the proliferation of residual Her2-positive tumor cell populations that survive T-DM1.

Conclusions:

CDK4/6 is a viable therapeutic target in HER2-positive breast cancer models that functions downstream of Her2. Tissue based markers are available to direct rational utilization of PD-0332991. Clinical studies of CDK4/6 inhibition in combination with Her2-targeted therapies have commenced.

Disclosure:

E. Knudsen: The author is on an advisory board and receives sponsored research funding from Pfizer.

All other authors have declared no conflicts of interest.