Bhin, Jinhyuk; Paes Dias, Mariana; Gogola, Ewa; Rolfs, Frank; Piersma, Sander R; de Bruijn, Roebi; de Ruiter, Julian R; van den Broek, Bram; Duarte, Alexandra A; Sol, Wendy; van der Heijden, Ingrid; Andronikou, Christina; Kaiponen, Taina S; Bakker, Lara; Lieftink, Cor; Morris, Ben; Beijersbergen, Roderick L; van de Ven, Marieke; Jimenez, Connie R; Wessels, Lodewyk F A; ... (2023). Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors. Cell reports, 42(5), p. 112538. Cell Press 10.1016/j.celrep.2023.112538
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1-s2.0-S2211124723005491-main.pdf - Published Version Available under License Creative Commons: Attribution (CC-BY). Download (7MB) | Preview |
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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