Abstract P2-04-01: Cyclin dependent kinase 7 ( CDK7) inhibition promotes genomic instability and mitotic catastrophe in triple negative breast cancer

Abstract

Abstract Triple negative breast cancer (TNBC) is highly proliferative and genomically unstable, making these tumors particularly sensitive to anti-proliferative chemotherapies. For nearly 20 years, inhibitors of cyclin/cyclin dependent kinases (CDK) that target proliferation have been investigated for the treatment of a myriad of neoplasms with limited success due to dose limiting toxicities as a result of generally targeting CDKs. Agents that can selectively target proliferation and mitosis within cancer cells without inducing systemic toxicity should greatly improve patient outcomes from TNBC. Recently, selective CDK7 inhibitors have entered clinical trials for solid tumors promising to diminish toxicity by primarily inhibiting CDK7. Due to resistance mechanisms that will inevitably manifest during treatment, understanding the pathways controlled by CDK7 inhibition is imperative. CDK7 forms a complex with MAT1 and cyclin H to phosphorylate serine 2 and 7 on the C terminal domain of RNA Polymerase II and promote pause release during transcription of TNBC driver genes. With selective covalent CDK7 inhibitors such as THZ1, RNA Polymerase II remains un-phosphorylated reducing the expression of genes necessary for mitosis, proliferation and viability. While this has been proposed to be due to inhibition of super-enhancer function, we show here that inhibition of CDK7 increases genomic instability of TNBC cell lines by promoting multi-nucleation and micro-nucleation. This is associated with an arrest at G2/M as well as the suppression of mitosis-related gene expression. Together, these data reveal that the mechanism of action of CDK7 inhibitors is similar to conventional anti-mitotics. Because resistance mechanisms frequently occur in cancer settings, we also generated two models of resistance to CDK7 inhibitors using the TNBC models, MDA-MB-231 and MDA-MB-468. We show the transporter ABCG2 can be up-regulated with the development of resistance and that inhibition of this transporter restores sensitivity to CDK7 inhibition. These data suggest that blockade of multi-drug resistance proteins such as ABCG2, may be useful for ensuring responsiveness to CDK7 inhibitors. Further analysis of gene expression changes occurring in response to such inhibitors should reveal additional key target genes that define therapeutic response in this disease. Understanding the full effects of CDK7 inhibition and resistance mechanisms may lead to a selective approach for targeting proliferation of TNBC and improving patient outcomes from this disease. Citation Format: Bryan M Webb, Melyssa Shively, Katrina Piemonte, Jennifer M Sahni, Ruth A Keri. Cyclin dependent kinase 7 ( CDK7) inhibition promotes genomic instability and mitotic catastrophe in triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-04-01.