Abstract P4-07-06: Cyclin dependent kinase 7 (CDK7) inhibition with THZ1 induces mitotic failure and increases genomic instability 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. While efficacious, these drugs induce dose limiting toxicities. Agents that can selectively target proliferation within cancer cells without inducing systemic toxicity should greatly improve patient outcomes from TNBC. In this regard, we have found that TNBC cells are particularly vulnerable to suppression of the transcriptional regulator, LIN9, that controls cell cycle progression. LIN9 mRNA is overexpressed in 66% of TNBCs and is correlated with worse patient outcomes. Moreover, suppression of LIN9 expression induces multi-nucleation, micronucleation, mitotic catastrophe, and cell death and/or senescence. While transcription factors are generally considered “undruggable, LIN9 expression can be pharmacologically suppressed by blocking the activity of cyclin dependent kinase 7 (CDK7) with the selective, covalent CDK7 inhibitor, THZ1. CDK7 inhibitors inactivate RNA polymerase 2 and destabilize the super-enhancer mediated expression of oncogenes. Treatment of three TNBC cell lines (MDA-MB-231, MDA-MB-468, and HCC38) with THZ1 induces G2/M arrest and phenocopies genetic silencing of LIN9. Use of live cell imaging revealed that THZ1 increases the duration of mitosis and also leads to mitosis-associated cell death. Together, these data reveal that CDK7 inhibitors primarily inhibit TNBC growth by causing mitotic dysfunction and potentiating genomic instability by inducing micro- and multi-nucleation. In addition, they suggest that suppressing LIN9 expression by inhibiting CDK7 may lead to a selective approach for targeting proliferation of TNBC and improving patient outcomes from this disease. Citation Format: Webb BM, Sahni JM, Keri RA. Cyclin dependent kinase 7 (CDK7) inhibition with THZ1 induces mitotic failure and increases genomic instability in triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-07-06.