Targeting ataxia telangiectasia mutated and Rad3 related kinase (ATR) in PTEN deficient breast cancers for personalized therapy

Al-Subhi, Nouf and Ali, Reem and Abdel-Fatah, Tarek and Moseley, Paul M. and Chan, Stephen Y.T. and Green, Andrew R. and Ellis, Ian O. and Rakha, Emad and Madhusudan, Srinivasan (2018) Targeting ataxia telangiectasia mutated and Rad3 related kinase (ATR) in PTEN deficient breast cancers for personalized therapy. Breast Cancer Research and Treatment . ISSN 1573-7217 (In Press)

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Abstract

Purpose: PTEN, a negative regulator of PI3K signaling, is involved in DNA repair. ATR is a key sensor of DNA damage and replication stress. We evaluated whether ATR signaling has clinical significance and could be targeted by synthetic lethality in PTEN deficient triple negative breast cancer (TNBC).

Methods: PTEN, ATR and pCHK1Ser345 protein level was evaluated in 1650 human breast cancers. ATR blockade by VE-821 was investigated in PTEN-proficient (MDAMB-231) and PTEN-deficient (BT-549, MDA-MB-468) TNBC cell lines. Functional studies included DNA repair expression profiling, MTS cell-proliferation assay, FACS (cell cycle progression & γH2AX accumulation) and FITC-annexin V flow cytometry analysis.

Results: Low nuclear PTEN was associated with higher grade, pleomorphism, dedifferentiation, higher mitotic index, larger tumour size, ER negativity, and shorter survival (p values <0.05). In tumours with low nuclear PTEN, high ATR and/or high pCHK1ser345 level was also linked to higher grade, larger tumour size and poor survival (all p values <0.05). VE-821 was selectively toxic in PTEN deficient TNBC cells and resulted in accumulation of double strand DNA breaks, cell cycle arrest, and increased apoptosis.

Conclusion: ATR signalling adversely impact survival in PTEN deficient breast cancers. ATR inhibition is synthetically lethal in PTEN deficient TNBC cells.

Item Type: Article
Keywords: Breast cancer; biomarker; PTEN; ATR; Triple negative breast cancer; Synthetic lethality
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Division of Cancer and Stem Cells
Depositing User: Eprints, Support
Date Deposited: 23 Jan 2018 09:48
Last Modified: 24 Jan 2018 06:45
URI: http://eprints.nottingham.ac.uk/id/eprint/49279

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