Bhin, JinhyukJinhyukBhinPaes Dias, MarianaMarianaPaes DiasGogola, EwaEwaGogolaRolfs, FrankFrankRolfsPiersma, Sander RSander RPiersmade Bruijn, RoebiRoebide Bruijnde Ruiter, Julian RJulian Rde Ruitervan den Broek, BramBramvan den BroekDuarte, Alexandra AAlexandra ADuarteSol, WendyWendySolvan der Heijden, IngridIngridvan der HeijdenAndronikou, ChristinaChristinaAndronikou0000-0003-4845-8398Kaiponen, Taina SusannaTaina SusannaKaiponenBakker, LaraLaraBakkerLieftink, CorCorLieftinkMorris, BenBenMorrisBeijersbergen, Roderick LRoderick LBeijersbergenvan de Ven, MariekeMariekevan de VenJimenez, Connie RConnie RJimenezWessels, Lodewyk F ALodewyk F AWesselsRottenberg, SvenSvenRottenberg0000-0003-2044-9844Jonkers, JosJosJonkers2024-10-252024-10-252023-05-30https://boris-portal.unibe.ch/handle/20.500.12422/167256BRCA1 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.enBRCA1 BRCA2 CP: Cancer PARP inhibitor breast cancer homologous recombination multi-omics therapy resistance600 - Technology::610 - Medicine & health600 - Technology::630 - Agriculturearticle10.48350/1827123720909510.1016/j.celrep.2023.112538