Genes & Cancer

CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models

Agnieszka K. Witkiewicz1,2, Derek Cox1, Erik S. Knudsen1,2

1 Department of Pathology , Simmons Cancer Center, Dalls, TX

2 Department of Pathology, UT Southwestern, Dallas, TX


Erik S. Knudsen, email:


Agnieszka K. Witkiewicz, email:

Keywords: RB, HER2, Palbocicllb, CDK4, T-DM1

Received: August 2, 2014 Accepted: August 6, 2014 Published: August 7, 2014


In spite of the efficacy of Her2-targeted therapies, recurrence and progression remain a challenge for treatment of Her2 positive breast cancer. CDK4/6 function downstream of Her2; therefore, inhibition of these kinases could represent an important therapeutic approach to augment the effectiveness of standard therapies. In models of acquired resistance to Her2-targeted therapies, Cyclin D1 was inappropriately activated and CDK4/6 inhibition was effective at blocking proliferation by targeting this common pathway associated with resistance. These data were recapitulated in Her2 positive xenografts. Furthermore, in a series of 35 primary breast tumor explants, treatment with PD-0332991 resulted in a greater than 4-fold suppression of the Ki67. The effects of CDK4/6 inhibition 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. Combination studies illustrated that CDK4/6 inhibition is cooperative with multiple Her2-targeted agents and provides a complementary mechanism of action to T-DM1 to efficiently suppresses the proliferation of residual Her2-positive tumor cell populations that survive T-DM1. Together, these data indicate CDK4/6 is a viable therapeutic target that functions downstream of Her2, and tissue based markers are available to direct rational utilization of CDK4/6 inhibitors in combination with Her2-targeted agents.

PII: 24