Abstract P1-09-04: Activity of CT7001 an orally bio-available cyclin-dependent kinase 7 selective inhibitor in models of triple negative breast cancer
Authors: AK Bahl, E Einscow, A Leishman, E Sullivan, S Ali, RC Coombes, AGM Barrett, B Li, WM Gallagher, NO Carragher, T Patel
Journal: Cancer Research (2018)

Abstract Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous subtype of breast cancer that commonly exhibit poor prognosis and high relapse rates at early stages after conventional neoadjuvant chemotherapy. CDK7 inhibition has emerged as an 'Achilles heel' in TNBC via blocking transcriptional addiction to a defined cluster of genes (Wang et al 2015). CDK7 acts as a CDK-activating kinase controlling proliferation and as a transcriptional kinase phosphorylating RNA Polymerase II. Eukaryotic RNA polymerase II (Pol II) is a 12-subunit DNA-dependent RNA polymerase that is responsible for transcribing nuclear genes encoding messenger RNAs and several small nuclear RNAs (R Young 1991) We have demonstrated that established cell-lines and patient derived tumour tissue (PDTT, explants established as models at low passage numbers that have not been grown in plastic or propagated as cell cultures) of TNBC are sensitive to a potent, selective and orally bioavailable CDK7 inhibitor CT7001 (ICEC0942). CT7001 produces a concentration-dependent inhibition of growth with GI50s &amp;lt;1 micromolar across all TNBC cells tested to-date. The inhibition of proliferation was associated with an inhibition of c-MYC, Mcl-1 and phospho-Pol II as determined by Western Blot analysis. This demonstrates that CT7001 effectively controls transcriptional regulation and anti-apoptotic mechanisms in a diverse group of TNBC cellular models. CT7001 was also evaluated in an in vivo orthotopic-PDX model of TNBC in nu/nu mice. Establishing PDX-xenograft tumour models from PDTT at low passage is believed to conserve original tumour characteristics such as heterogeneous histology, clinical biomolecular signature, malignant phenotypes and genotypes. Therefore, patient-derived tumour grafts are believed to offer relevant predictive insights into clinical outcomes when evaluating the efficacy of novel cancer therapies. Orally administered CT7001 monotherapy produced strong and sustained regression of the tumour that persisted during the dosing schedule and strong suppression was still maintained upon cessation of treatment. At doses that produced regression CT7001 was well tolerated with little effect on body weight loss (&amp;lt;10%). CT7001 is a potent, selective and orally bioavailable inhibitor of CDK7 that shows promise as a potential new treatment for TNBC. References Richard A. Young Annual Review of Biochemistry. 1991 60 (1): 689–715 Wang et al Cell. 2015 163(1):174-86. Citation Format: Bahl AK, Einscow E, Leishman A, Sullivan E, Ali S, Coombes RC, Barrett AGM, Li B, Gallagher WM, Carragher NO, Patel T. Activity of CT7001 an orally bio-available cyclin-dependent kinase 7 selective inhibitor in models of triple negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-09-04.