Targeting CCNE1-High Breast Cancers with CDK2 Inhibitor INCB123667: A New Therapeutic Approach

CDK4/6 inhibitors are recognized for their role in treating metastatic ER+ HER2- breast cancer, either alone or with hormone therapy. However, resistance to these treatments is common due to factors like Rb loss, heightened CDK4/6 activity, and increased expression and function of CDK2/Cyclin E1. This leads to a significant clinical demand for alternative approaches.

Triple-negative breast cancers (TNBC) are particularly challenging due to the absence of hormone receptors and their diversity, making them resistant to current treatments. Overexpression or amplification of CCNE1 is linked to poor outcomes in various cancers, including those of the ovary, stomach, uterus, and ER+ breast. These cancers are reliant on CDK2 for growth and survival, with CDK2 and CCNE1 working together to phosphorylate Rb and promote cell cycle progression.

A study utilized INCB123667, a potent and selective CDK2 inhibitor, to show its effectiveness against CCNE1-high breast cancer models. CRISPR screening data revealed a subset of these models, including TNBC and different subtypes of ER+ HER2- and HR- HER2+ cancers, that are reliant on CDK2.

Two cell lines, HCC1569 and MDAMB157, were tested and showed sensitivity to INCB123667 but not to various CDK4/6 inhibitors. INCB123667 was found to be highly effective against CDK2 at subnanomolar levels and did not affect other CDKs. It induced senescence in CCNE1-high HCC1569 cells but had no effect on non-amplified cell lines like MCF7 and T47D.

Significant tumor growth inhibition was observed in CCNE1-high patient-derived xenograft (PDX) and xenograft models with minimal weight loss. The study also identified a gene signature linked to cell cycle regulation that differed from CDK4/6 responsive genes.

In summary, the research highlights the potential of CDK2 inhibition with INCB123667, a CDK2 inhibitor in clinical development, for treating CCNE1-high ER+ HER2- and TNBC breast cancers. The treatment showed promise in inhibiting cell growth and tumor activity both in vitro and in vivo.

Acknowledgments go to Pharmaron, Crown Bioscience, and Champions Oncology for their R&D contributions.