RT Journal Article
SR Electronic
T1 The CDK7 inhibitor CT7001 (Samuraciclib) targets proliferation pathways to inhibit advanced prostate cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.29.497030
DO 10.1101/2022.06.29.497030
A1 Theodora A. Constantin
A1 Anabel Varela-Carver
A1 Kyle K. Greenland
A1 Gilberto Serrano de Almeida
A1 Lucy Penfold
A1 Simon Ang
A1 Alice Ormrod
A1 Edward K. Ainscow
A1 Ash K. Bahl
A1 David Carling
A1 Matthew J. Fuchter
A1 Simak Ali
A1 Charlotte L. Bevan
YR 2022
UL http://biorxiv.org/content/early/2022/06/29/2022.06.29.497030.abstract
AB Background Current strategies to inhibit the androgen receptor (AR) are circumvented in castration-resistant prostate cancer (CRPC). Cyclin-dependent kinase 7 (CDK7) promotes AR signalling, in addition to established roles in cell cycle and global transcription regulation, together, providing a rationale for its therapeutic targeting in CRPC.Methods The antitumour activity of CT7001, an orally bioavailable CDK7 inhibitor, was investigated across CRPC models in vitro and in xenograft models in vivo. Cell-based assays and transcriptomic analyses of treated xenografts were employed to investigate the mechanism driving activity of CT7001, alone and in combination with the antiandrogen enzalutamide.Results CT7001 selectively engages with CDK7 in prostate cancer cells, causing inhibition of proliferation and cell cycle arrest. Activation of p53, induction of apoptosis, and suppression of transcription mediated by full-length and constitutively active AR splice variants contribute to antitumour efficacy in vitro. Oral administration of CT7001 represses growth of CRPC xenografts and significantly augments growth inhibition achieved by enzalutamide. Transcriptome analyses of treated xenografts indicate cell cycle and AR inhibition as the mode of action of CT7001 in vivo.Conclusions This study supports CDK7 inhibition as a strategy to target deregulated cell proliferation and demonstrates CT7001 is a promising CRPC therapeutic, alone or in combination with AR-targeting compounds.Competing Interest StatementG.S.A. has previously been supported by a research grant from Carrick Therapeutics Ltd to C.L.B. S. Ali is a named inventor on CDK7 inhibitor patents that have been licensed to Carrick Therapeutics Ltd, has received royalty payments, shares, and research funding from Carrick Therapeutics. M.J.F. is a named inventor on CDK7 inhibitor patents that have been licensed to Carrick Therapeutics Ltd and has received royalty payments from Carrick Therapeutics. A.K.B. and E.C. are/were at the time of this study employees of Carrick Therapeutics. The following authors declare that they have no competing interests: T.A.C., A.V.C., K.K.G., L.P., S. Ang, A.O., D.C..ARandrogen receptorAR-Vandrogen receptor variantASTaspartate aminotransferaseCAKCDK-activating kinaseCDKcyclin-dependent kinaseCeTSAcellular thermal shift assayCRPCcastration-resistant prostate cancerCTDC-terminal domainDMSOdimethylsulfoxideFCSfoetal calf serumFDRfalse discovery rateFL-ARfull-length androgen receptorGRgrowth-rateGSEAgene set enrichment analysisLBDligand-binding domainPadjadjusted p-valuePBSphosphate buffered salinePCAprincipal component analysisPolIIRNA polymerase IIPSAprostate-specific antigenP-TEFbpositive transcription elongation factor bRbretinoblastomaRT-qPCRquantitative reverse transcription PCRSRBsulforhodamine B