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

被引：25

作者：

Bhin, Jinhyuk ^{[1
,2
,3
]}

Dias, Mariana Paes ^{[1
]}

Gogola, Ewa ^{[1
]}

Rolfs, Frank ^{[1
,4
]}

Piersma, Sander R. ^{[4
]}

de Bruijn, Roebi ^{[1
,2
]}

de Ruiter, Julian R. ^{[1
,2
]}

van den Broek, Bram ^{[5
]}

Duarte, Alexandra A. ^{[1
]}

Sol, Wendy ^{[1
]}

van der Heijden, Ingrid ^{[1
]}

Andronikou, Christina ^{[1
,6
,7
]}

Kaiponen, Taina S. ^{[6
,7
]}

Bakker, Lara ^{[1
]}

Lieftink, Cor ^{[2
]}

Morris, Ben ^{[2
]}

Beijersbergen, Roderick L. ^{[2
]}

van de Ven, Marieke ^{[8
]}

Jimenez, Connie R. ^{[4
]}

Wessels, Lodewyk F. A. ^{[2
]}

Rottenberg, Sven ^{[1
,6
,7
]}

Jonkers, Jos ^{[1
]}

机构：

[1] Netherlands Canc Inst, Oncode Inst, Div Mol Pathol, NL-1066 CX Amsterdam, Netherlands

[2] Netherlands Canc Inst, Oncode Inst, Div Mol Carcinogenesis, NL-1066 CX Amsterdam, Netherlands

[3] Yonsei Univ, Gangnam Severance Hosp, Coll Med, Dept Biomed Syst Informat, Seoul 03722, South Korea

[4] Amsterdam UMC, Dept Med Oncol, OncoProte Lab, NL-1081 HV Amsterdam, Netherlands

[5] Netherlands Canc Inst, Oncode Inst, Div Cell Biol, NL-1066 CX Amsterdam, Netherlands

[6] Univ Bern, Canc Therapy Resistance Cluster & Bern Ctr Precis, Dept Biomed Res, CH-3088 Bern, Switzerland

[7] Univ Bern, Inst Anim Pathol, Vetsuisse Fac, CH-3012 Bern, Switzerland

[8] Netherlands Canc Inst, Mouse Clin Canc & Aging, Preclin Intervent Unit, NL-1066 CX Amsterdam, Netherlands

来源：

CELL REPORTS | 2023年 / 42卷 / 05期

基金：

瑞士国家科学基金会; 欧洲研究理事会;

关键词：

HOMOLOGOUS RECOMBINATION; DNA-REPAIR; SYNTHETIC LETHALITY; REPLICATION FORKS; LUNG-CANCER; INHIBITOR; MUTATIONS; GENES; BRCA1; END;

D O I：

10.1016/j.celrep.2023.112538

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 poten-tially involved in modulating PARPi response.

引用

页数：24

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