title: CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models.
abstract: In spite of the efficacy of Her2-targeted therapies, recurrence and progression remain a challenge for treatment of Her2 positive breast cancer. CDK4/6 controls pathway downstream of Her2, 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.
authors.affiliation: Department of Pathology, Simmons Cancer Center, Dalls, TX ; Department of Pathology, UT Southwestern, Dallas, TX.
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Witkiewicz
authors.affiliation: Department of Pathology, Simmons Cancer Center, Dalls, TX.
authors.forename: Derek
authors.initials: D
authors.lastname: Cox
authors.affiliation: Department of Pathology, Simmons Cancer Center, Dalls, TX ; Department of Pathology, UT Southwestern, Dallas, TX.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
keywords: CDK4; HER2; Palbocicllb; RB; T-DM1