Abstract LB-158: Simultaneous targeting of the cell cycle and transcription through irreversible inhibition of CDK7: a novel, new therapeutic approach for high-grade glioma

Abstract

Abstract High Grade Glioma (HGG), an incurable aggressive neoplasm of the brain, is characterised by a diverse array of genetic aberrations including those associated with receptor tyrosine kinase (RTK) signalling and cell cycle regulation pathways. Furthermore, HGG possess a highly heterogeneous intratumoral transcriptional profile, both at the global and subclonal levels, that allows for rapid resistance to a wide spectrum of therapeutics. Cyclin dependent kinase 7 (CDK7) presents an opportunity to target proliferation and global transcription simultaneously as it is the CDK activating kinase that controls multiple checkpoint progressions through the cell cycle as well as stabilising the RNA polymerase II-based transcriptional apparatus. Using a new irreversible inhibitor of CDK7, THZ1, we demonstrate that a panel of 10 patient-derived primary HGG cells lines, representing a diverse array of genotypes and phenotypes, were all exquisitely sensitive to THZ1 treatment at low nanomolar doses. THZ1 induced global transcription downregulation as measured by microarray analysis and resulted in potent caspase 3/7 activation, DNA damage and apoptosis. Cell cycle in all lines was arrested at the G2/M phase regardless of p53, CDKN2A/B or RB status, with substantial aneuploidy observed. Additionally, THZ1 treatment results in the dramatic loss of several RTKs critical in driving HGG including EGFR, EGFRvIII, PDGFR-α, PDGFR-β, MET, FGFR-3 and AXL, resulting in reduced PI3K/AKT, MAPK/ERK and STAT3 activation. Efficacy in ex vivo tumor slices and in vivo orthotopic experiments will be presented as well as insights into possible mechanisms of resistance. Our work suggest that irreversible inhibition of CDK7 represents a novel and effective treatment for HGG. Citation Format: Sameer Greenall, Terrance G. Johns. Simultaneous targeting of the cell cycle and transcription through irreversible inhibition of CDK7: a novel, new therapeutic approach for high-grade glioma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-158.