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.

ESE-1 Knockdown Attenuates Growth in Trastuzumab-resistant HER2+ Breast Cancer Cells

“…In a doxycycline inducible MMTV-HER2 murine model, recurrent tumors had high expression of cyclin D1/CDK4 proteins resulting in cyclin D1/CDK4-mediated resistance to targeted therapy for HER2 + . This was overcome using CDK4/6 inhibitors 17,18 . These by-pass mechanisms contribute to clinical morbidity and mortality, due to relapse of trastuzumab-resistant breast cancer.…”

Genomic profiling of multiple sequentially acquired tumor metastatic sites from an “exceptional responder” lung adenocarcinoma patient reveals extensive genomic heterogeneity and novel somatic variants driving treatment response

“…On the other hand, in the metastatic lymph node, the CDK2 pathway may have been affected by amplification and overexpression of CCNE1 . In models of acquired resistance to ERBB2-targeted therapies, cyclin D1 was shown to be deregulated and CDK4/6 inhibition was effective at overcoming such resistance (Witkiewicz et al 2014). However, tumors with deregulated expression of CCNE1 would be resistant to such targeted agents, suggesting that treatment with CDK2 inhibitors may be a valid strategy in such patients (Scaltriti et al 2011).…”

The history and future of targeting cyclin-dependent kinases in cancer therapy

“…CDK4 and CDK6 inhibition antagonizes the effect of cytotoxic chemotherapy and radiotherapy because the vast majority of cytotoxic chemotherapies require cells to be cycling 179-181 . Despite this requirement, several studies are underway to evaluate scheduling with CDK4 and CDK6 inhibition, following the concept that release from CDK4 and CDK6 inhibition may synchronize cells and thereby sensitize cancer cells to a subsequent cytotoxic treatment, or may prevent ongoing proliferation or re-population of cancer cells between cytotoxic administrations 182 . Although such scheduling approaches have been shown to be potentially beneficial in preclinical models, translating this to the clinic, where proliferation rates of tumours are highly variable, will be challenging.…”