59O - Targeting CDK4/6 in Her2 positive breast cancer: Therapeutic effect, markers, and combination strategies
|Date||08 May 2014|
|Session||Best abstracts session|
|Topics|| Drug Development
|Citation||Annals of Oncology (2014) 25 (suppl_1): i21-i22. 10.1093/annonc/mdu069|
E. Knudsen1, D. Cox2, J. Franco2, A. Frankel3, B. Haley4, A. Witkiewicz2
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.
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.
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.
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.
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.