PPP2R1A mutations cause ATR inhibitor sensitivity in ovarian clear cell carcinoma.

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ICR Authors

Krastev, Dragomir
 Song, Feifei
 Natrajan, Rachael
 Roumeliotis, Theodoros
 Choudhary, Jyoti
 Yeung, Chit Sum Jason
 Pettitt, Stephen
 Tutt, Andrew
 Lord, Christopher

Authors

Stewart, J
Krastev, DB
Brough, R
Zatreanu, D
Song, F
Baxter, JS
Sridhar, S
Frankum, J
Konde, A
Yang, W
Haider, S
Alexander, J
Betteridge, K
Gulati, A
Attygalle, AD
Vroobel, K
Natrajan, R
Khalique, S
Roumeliotis, TI
Choudhary, JS
Yeung, J
Wicks, AJ
Marlow, R
Banerjee, S
Pettitt, SJ
Tutt, ANJ
Lord, CJ

Document Type

Journal Article

Date

2025-03-17

Date Accepted

2024-12-12

Abstract

Identification of ARID1A/ATR synthetic lethality led to ATR inhibitor phase II trials in ovarian clear cell carcinoma (OCCC), a cancer of unmet need. Using multiple CRISPR-Cas9 mutagenesis and interference screens, we show that inactivation of protein phosphatase 2A (PP2A) subunits, including PPP2R1A, enhance ATRi sensitivity in ARID1A mutant OCCC. Analysis of a new OCCC cohort indicates that 52% possess oncogenic PPP2R1A p.R183 mutations and of these, one half possessed both ARID1A as well as PPP2R1A mutations. Using CRISPR-prime editing to generate new isogenic models of PPP2R1A mutant OCCC, we found that PPP2R1A p.R183W and p.R183P mutations cause ATRi-induced S phase stress, premature mitotic entry, genomic instability and ATRi sensitivity in OCCC tumour cells. p.R183 mutation also enhanced both in vitro and in vivo ATRi sensitivity in preclinical models of ARID1A mutant OCCC. These results argue for the assessment of PPP2R1A mutations as a biomarker of ATRi sensitivity.

Citation

Oncogene, 2025,

DOI

10.1038/s41388-024-03265-0

URI

https://repository.icr.ac.uk/handle/internal/6575

Rights

http://creativecommons.org/licenses/by/4.0/

Source Title

Oncogene

Publisher

SPRINGERNATURE

ISSN

0950-9232

eISSN

1476-5594

Collections

Breast Cancer Research

Research Team

Gene Function
Functional Genomics
Functional Proteomics
Prote & Metabolomics Fac
Target Vali & DNA Dam Res
Directorate Breast Canc

Notes