Inhibition of BRCT(BRCA1)-phosphoprotein interaction enhances the cytotoxic effect of olaparib in breast cancer cells: a proof of concept study for synthetic lethal therapeutic option.

Breast Cancer Research and Treatment
Ziyan Yuan PessettoAmarnath Natarajan

Abstract

Synthetic lethal therapeutic strategy using poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor olaparib in carriers of BRCA1 or BRCA2 mutation has shown promise in clinical settings. Since <5 % of patients are BRCA1 or BRCA2 mutation carriers, small molecules that functionally mimic BRCA1 or BRCA2 mutations will extend the synthetic lethal therapeutic option for non-mutation carriers. Here we provide proof of principle for this strategy using a BRCA1 inhibitor peptide 2 that targets the BRCT(BRCA1)-phosphoprotein interaction and mimics the M177R/K BRCA1 mutation. Reciprocal immunoprecipitation and immunoblotting of BRCA1 and Abraxas was used to demonstrate inhibitor 2 targets BRCT(BRCA1)-Abraxas interface. Immunostaining of γH2AX, cell cycle analysis and homologous recombination (HR) assays were conducted to confirm that inhibitor 2 functionally mimics a chemosensitizing BRCA1 mutation. The concept of synthetic lethal therapeutic strategy with the BRCA1 inhibitor 2 and the PARP inhibitor Olaparib was explored in HeLa, MDA-MB-231, and HCC1937 cell lines. The results show that inhibition of BRCA1 by 2 sensitizes HeLa and MDA-MB-231 cells but not HCC1937 to Olaparib mediated growth inhibition and apoptosis. These...Continue Reading

References

Nov 23, 2000·Proceedings of the National Academy of Sciences of the United States of America·P A WenderJ B Rothbard
Jan 26, 2002·Molecular and Cellular Biology·Bo XuMichael B Kastan
Oct 25, 2003·Science·Isaac A MankeMichael B Yaffe
Oct 25, 2003·Science·Xiaochun YuJunjie Chen
Jan 15, 2005·Proceedings of the National Academy of Sciences of the United States of America·Koji NakanishiMaria Jasin
May 26, 2007·Science·Bijan SobhianRoger A Greenberg
Aug 10, 2007·Journal of the American Chemical Society·G L LokeshAmarnath Natarajan
Jun 26, 2009·The New England Journal of Medicine·Peter C FongJohann S de Bono
Feb 4, 2010·Biochemical and Biophysical Research Communications·Prem Raj B JosephAmarnath Natarajan
Jul 21, 2010·Annals of Oncology : Official Journal of the European Society for Medical Oncology·C UnderhillH Bonnefoi
Oct 20, 2010·Nature Reviews. Clinical Oncology·Steven A Narod
Nov 3, 2011·ACS Medicinal Chemistry Letters·Ziyan YuanAmarnath Natarajan

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Citations

Jul 31, 2013·Mutation Research·Inbal Mermershtain, J N Mark Glover
Oct 15, 2014·Nature Reviews. Genetics·Raphaël Rodriguez, Kyle M Miller
Feb 5, 2014·Expert Opinion on Therapeutic Targets·João F S Carvalho, Roland Kanaar
Jul 28, 2015·Expert Opinion on Drug Discovery·Ahmed KamalMohammed Shaheer Malik
Dec 4, 2012·Experimental Cell Research·Kevin W Caestecker, Gerlinde R Van de Walle
Feb 6, 2015·ACS Chemical Biology·E Railey WhiteMatthew C T Hartman
Apr 15, 2015·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Nagsen GautamYazen Alnouti
Aug 15, 2014·Journal of Medicinal Chemistry·Sandeep RanaAmarnath Natarajan
Oct 1, 2013·Biochemistry·Xuying Liu, John A A Ladias
Jul 29, 2017·PLoS Genetics·Rolando RuizAnand K Ganesan
Apr 15, 2017·Oncotarget·Jamie L ArnstYing Yan
Aug 6, 2020·The Journal of Biological Chemistry·Xiuhua LiuXiaochun Yu
Sep 17, 2020·International Journal of Molecular Sciences·Samuele LodovichiAlvaro Galli
Jan 11, 2020·Frontiers in Oncology·Anika Trenner, Alessandro A Sartori
Jul 30, 2021·DNA Repair·Ujjayinee Ray, Sathees C Raghavan

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