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An Inducible BRCA1 Expression System with In Vivo Applicability Uncovers Activity of the Combination of ATR and PARP

Elsa Irving1, Alaide Morcavallo1, Jekaterina Vohhodina-Tretjakova1

  • 1Bioscience, Oncology Targeted Discovery, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, UK.

Cancers
|January 28, 2026
PubMed
Abstract

Insights

A BRCA1 variant, ∆exon11, confers partial resistance to PARPi by restoring homologous recombination repair (HRR). Combining PARPi with ATR inhibitors overcomes this resistance, offering a new therapeutic strategy for BRCA1-mutant cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Poly(ADP-ribose) polymerase inhibitors (PARPi) are effective against homologous recombination repair (HRR) deficient cancers, particularly those with BRCA1/2 mutations.
  • Therapeutic resistance to PARPi is a significant clinical challenge.
  • The role of BRCA1 hypomorphic variants in PARPi resistance is not well understood.

Purpose of the Study:

  • To investigate the impact of distinct BRCA1 hypomorphic variants on PARPi sensitivity.
  • To elucidate the mechanism of resistance mediated by the ∆exon11 BRCA1 variant.
  • To identify potential combination therapies to overcome PARPi resistance.

Main Methods:

  • Engineered a doxycycline-inducible BRCA1 expression system in a BRCA1-mutant triple-negative breast cancer cell line (MDAMB436).
  • Assessed the in vitro and in vivo effects of various BRCA1 variants, including ∆exon11, on drug sensitivity and HRR.
  • Measured HRR restoration by RAD51 foci formation and interaction with repair partners like PALB2.
  • Evaluated the efficacy of combining olaparib with the ATR inhibitor ceralasertib.

Main Results:

  • Overexpression of the ∆exon11 BRCA1 hypomorph conferred resistance to olaparib and carboplatin in a dose-dependent manner.
  • ∆exon11 BRCA1 partially restored HRR, but less efficiently than full-length BRCA1, evidenced by reduced RAD51 foci and PALB2 interaction.
  • Tumors expressing ∆exon11 BRCA1 showed only partial resistance to olaparib in vivo.
  • The combination of olaparib and ceralasertib effectively overcame ∆exon11-mediated resistance and impaired RAD51 foci formation.

Conclusions:

  • The ∆exon11 BRCA1 hypomorph mediates a dose-dependent, partial restoration of HRR, explaining variable PARPi resistance in preclinical models.
  • ATR inhibition combined with PARPi represents a promising clinical strategy to counteract resistance driven by ∆exon11 BRCA1 hypomorphs.
Keywords:
BRCA hypomorphBRCA mutantPARP inhibitorsbreast cancercombination therapyresistance

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