Therapeutic rationale to target highly expressed CDK7 conferring poor outcomes in triple-negative breast cancer

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

Triple-negative breast cancer (TNBC) patients commonly exhibit poor prognosis and high relapse after treatment, but there remains a lack of biomarkers and effective targeted therapies for this disease. Here, we report evidence highlighting the cell-cycle–related kinase CDK7 as a driver and candidate therapeutic target in TNBC. Using publicly available transcriptomic data from a collated set of TNBC patients (n ¼ 383) and the METABRIC TNBC dataset (n ¼ 217), we found CDK7 mRNA levels to be correlated with patient prognosis. High CDK7 protein expression was associated with poor prognosis within the RATHER TNBC cohort (n ¼ 109) and the METABRIC TNBC cohort (n ¼ 203). The highly specific CDK7 kinase inhibitors, BS-181 and THZ1, each downregulated CDK7-mediated phosphorylation of RNA polymerase II, indicative of transcriptional inhibition, with THZ1 exhibiting 500-fold greater potency than BS-181. Mechanistic investigations revealed that the survival of MDA-MB-231 TNBC cells relied heavily on the BCL-2/BCL-XL signaling axes in cells. Accordingly, we found that combining the BCL-2/BCL-XL inhibitors ABT-263/ABT199 with the CDK7 inhibitor THZ1 synergized in producing growth inhibition and apoptosis of human TNBC cells. Collectively, our results highlight elevated CDK7 expression as a candidate biomarker of poor prognosis in TNBC, and they offer a preclinical proof of concept for combining CDK7 and BCL-2/BCL-XL inhibitors as a mechanism-based therapeutic strategy to improve TNBC treatment.

Detaljer

Författare
  • Bo Li
  • Triona Ni Chonghaile
  • Yue Fan
  • Stephen F. Madden
  • Rut Klinger
  • Aisling E. O'Connor
  • Louise Walsh
  • Gillian O'Hurley
  • Girish Mallya Udupi
  • Jesuchristopher Joseph
  • Finbarr Tarrant
  • Emer Conroy
  • Alexander Gaber
  • Suet-Feung Chin
  • Helen A Bardwell
  • Elena Provenzano
  • John P. Crown
  • Thierry Dubois
  • Sabine Linn
  • Carlos Caldas
  • Darran P. O'Connor
  • William M Gallagher
Enheter & grupper
Externa organisationer
  • University College Dublin
  • Royal College of Surgeons in Ireland
  • OncoMark Ltd
  • University of Cambridge
  • St Vincent's University Hospital
  • Curie Institute, Paris
  • Netherlands Cancer Institute
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi
Originalspråkengelska
Sidor (från-till)3834-3845
Antal sidor12
TidskriftCancer Research
Volym77
Utgivningsnummer14
StatusPublished - 2017 jul 15
PublikationskategoriForskning
Peer review utfördJa