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.
Highlights
Breast cancer is managed based on the presence of discrete markers that are measured clinically to direct patient care[1,2,3,4,5,6,7]
In the case of T-DM1, we demonstrated that CDK4/6 inhibition has a complementary mode of action to suppress the proliferation of residual clones of disease
In analysis of signaling downstream from HER2, we observed that Lapatinib treatment routinely down-regulates ERK activity in both SKBR3 and HER2/ MCF10A models, leading to the suppression of Cyclin D1 levels and the attenuation of E2F target genes such as MCM7 (Figure 1D)
Summary
Breast cancer is managed based on the presence of discrete markers that are measured clinically to direct patient care[1,2,3,4,5,6,7]. HER2 functions as a dimeric binding partner to activate other members of the epidermal growth factor receptor (EGFR) family These receptors signal through multiple pathways including ERK/ MAPK, PI3K/AKT, and JAK/STAT to stimulate tumor cell proliferation and survival[8]. HER2-positive breast cancers are typically addicted to this signaling, and are sensitive to inhibition of this pathway Agents, such as Lapatinib, Neratinib, and Afatanib are small molecules that bind to the tyrosine kinase domain of EGFR proteins and inhibit kinase activity to antagonize the activity of HER2 [8]. The antibody conjugate T-DM1, which was recently approved for late-stage HER2-positive disease, is Trastuzumab conjugated to the potent microtubule-poison metansine In this fashion, T-DM1 provides selective delivery of metansine to the tumor cells[16, 17]. Antibodies, conjugates, and smallmolecules have all been shown to provide clinical benefit and have received approval for treatment of different clinical manifestations of HER2-poisitve breast cancer[18,19,20]
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