Targeting cdk12/13 re-sensitizes trastuzumab resistant her2+breast cancers

Overexpression or amplification of the human epidermal growth factor receptor 2 (erbB2), which encodes for a receptor tyrosine kinase often referred to as HER2, occurs in about 20% breast cancer patients and is associated with aggressive disease and poor clinical outcome. The anti-HER2 therapy trastuzumab (a monoclonal antibody targeting HER2) has proven highly effective, increasing relapse free and overall survival for HER2 positive breast cancer patients. Nevertheless, acquisition of therapeutic resistance occurs frequently in advance disease. Recent studies have demonstrated that HER2 co-amplified genes may play a role in mechanisms of disease resistance. Cyclin dependent kinase 12 (CDK12) is among the genes that have been reported to be amplified in addition to HER2, and thus we aimed to investigate whether targeting CDK12 could be exploited as a therapeutic target and enhance and/or restore sensitivity in HER2 positive inhibitor resistant models of breast cancer. We have developed an in-house, highly selective, potent, and orally bioavailable CDK12/13 inhibitor, which effectively blocks proliferation and induces apoptosis in a panel of breast cancer cell lines and acts in synergy with trastuzumab in HER2 treatment resistant cell lines. Furthermore, our lead compound significantly slows tumor growth in trastuzumab resistant patient derived xenograft (PDX) models (as a single agent) and importantly, provokes greater efficacy in combination with trastuzumab. We are beginning to identify the signaling pathways underlying HER2 positive treatment resistance and how inhibition of CDK12/13 thwarts these resistance mechanisms. Accordingly, we anticipate that the development of CDK12/13 inhibitors holds promise as an anti-breast cancer strategy and future treatment option for HER2 positive breast cancer patients with recurrent disease. Citation Format: Francesca Vena, Max Aceti, Simon Bayle, Victor Quereda, Andrii Monastyrskyi, William Roush, Derek Duckett. Targeting cdk12/13 re-sensitizes trastuzumab resistant her2+ breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3051.