Targeting replicative stress and dna repair by combining parp and wee1 kinase inhibitors is synergistic in triple negative breast cancers with cyclin e or brca1 alteration

Xian Chen, Dong Yang, Jason P.W. Carey, Cansu Karakas, Constance Albarracin, Aysegul A. Sahin, Banu K. Arun, Merih Guray Durak, Mi Li, Mehrnoosh Kohansal, Tuyen N. Bui, Min Jin Ha, Kelly K. Hunt, Khandan Keyomarsi

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

The identification of biomarker‐driven targeted therapies for patients with triple negative breast cancer (TNBC) remains a major clinical challenge, due to a lack of specific targets. Here, we show that cyclin E, a major regulator of G1 to S transition, is deregulated in TNBC and is associated with mutations in DNA repair genes (e.g., BRCA1/2). Breast cancers with high levels of cyclin E not only have a higher prevalence of BRCA1/2 mutations, but also are associated with the worst out-comes. Using several in vitro and in vivo model systems, we show that TNBCs that harbor either mutations in BRCA1/2 or overexpression of cyclin E are very sensitive to the growth inhibitory effects of AZD‐1775 (Wee 1 kinase inhibitor) when used in combination with MK‐4837 (PARP inhib-itor). Combination treatment of TNBC cell lines with these two agents results in synergistic cell killing due to induction of replicative stress, downregulation of DNA repair and cytokinesis failure that results in increased apoptosis. These findings highlight the potential clinical application of using cyclin E and BRCA mutations as biomarkers to select only those patients with the highest repli-cative stress properties that may benefit from combination treatment with Wee 1 kinase and PARP inhibitors.

Original languageEnglish (US)
Article number1656
JournalCancers
Volume13
Issue number7
DOIs
StatePublished - Apr 1 2021

Keywords

  • BRCA
  • Cyclin E
  • DNA replication stress
  • Low molecular weight cyclin E (LMWE) PARP
  • Wee1 kinase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

MD Anderson CCSG core facilities

  • Advanced Technology Genomics Core
  • Cytogenetics and Cell Authentication Core

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