Abstract PD5-10: PD5-10 Dual therapeutic targeting of CDK8/19 and mTOR in triple negative breast cancer

Abstract

Abstract Triple negative breast cancer (TNBC) is the most aggressive subtype of all breast cancers. However, unlike other breast cancer subtypes, current treatments for TNBC are restricted and this scarcity of viable options is the key contributor to the poorer prognosis. Despite early response, almost all the targeted drugs tested in TNBC eventually fail due to the development of resistance. Patients’ data have shown that the expression level of Mediator kinases CDK8 and CDK19 are elevated in TNBC, and that higher expression of CDK8/19 is correlated with more advanced diseases and worse prognosis. Selective CDK8/19 inhibitor SNX631, when used as a single agent, inhibited the growth of several TNBC cell lines in vitro, cell-derived xenografts (CDXs) as well as patient derived xenografts (PDXs) in vivo, suggesting the potential of targeting CDK8/19 in treating TNBC. We also analyzed the effect of CDK8/19 inhibition on the outcome of treatment with mTORC1 inhibitor everolimus (RAD001), an approved drug for several cancers with mutations of PTEN or PI3KCA. SNX631 exhibited a synergistic effect in combination with everolimus on suppressing TNBC cell growth in vitro. In vivo treatment with everolimus alone achieved a strong tumor growth inhibition in TNBC xenograft models but all the tumors eventually resumed growth, indicated the development of resistance. Significantly, the addition of a CDK8/19 inhibitor prevented the emergence of in vivo everolimus resistance both in CDX and PDX tumors upon treatment for up to 150 days, suggesting a potential for extending remission or even achieving cures in TNBC. Transcriptomic analysis demonstrated that this effect was due to the prevention of transcriptional reprogramming associated with everolimus resistance in tumor cells. Citation Format: Xiaokai Ding, Hao Ji, Amanda C. Sharko, Juergen Loskutov, Zachary Mack, Jadyn Myers, Mengqian Chen, Elena Pugacheva, Igor Roninson, Eugenia Broude. PD5-10 Dual therapeutic targeting of CDK8/19 and mTOR in triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD5-10.