Cell Reports (May 2023)

Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors

  • Jinhyuk Bhin,
  • Mariana Paes Dias,
  • Ewa Gogola,
  • Frank Rolfs,
  • Sander R. Piersma,
  • Roebi de Bruijn,
  • Julian R. de Ruiter,
  • Bram van den Broek,
  • Alexandra A. Duarte,
  • Wendy Sol,
  • Ingrid van der Heijden,
  • Christina Andronikou,
  • Taina S. Kaiponen,
  • Lara Bakker,
  • Cor Lieftink,
  • Ben Morris,
  • Roderick L. Beijersbergen,
  • Marieke van de Ven,
  • Connie R. Jimenez,
  • Lodewyk F.A. Wessels,
  • Sven Rottenberg,
  • Jos Jonkers

Journal volume & issue
Vol. 42, no. 5
p. 112538

Abstract

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Summary: BRCA1 and BRCA2 both function in DNA double-strand break repair by homologous recombination (HR). Due to their HR defect, BRCA1/2-deficient cancers are sensitive to poly(ADP-ribose) polymerase inhibitors (PARPis), but they eventually acquire resistance. Preclinical studies yielded several PARPi resistance mechanisms that do not involve BRCA1/2 reactivation, but their relevance in the clinic remains elusive. To investigate which BRCA1/2-independent mechanisms drive spontaneous resistance in vivo, we combine molecular profiling with functional analysis of HR of matched PARPi-naive and PARPi-resistant mouse mammary tumors harboring large intragenic deletions that prevent reactivation of BRCA1/2. We observe restoration of HR in 62% of PARPi-resistant BRCA1-deficient tumors but none in the PARPi-resistant BRCA2-deficient tumors. Moreover, we find that 53BP1 loss is the prevalent resistance mechanism in HR-proficient BRCA1-deficient tumors, whereas resistance in BRCA2-deficient tumors is mainly induced by PARG loss. Furthermore, combined multi-omics analysis identifies additional genes and pathways potentially involved in modulating PARPi response.

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