RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer

被引：351

作者：

Cruz, C. ^{[1
,2
,3
]}

Castroviejo-Bermejo, M. ^{[1
]}

Gutierrez-Enriquez, S. ^{[4
]}

Llop-Guevara, A. ^{[1
]}

Ibrahim, Y. H. ^{[1
]}

Gris-Oliver, A. ^{[1
]}

Bonache, S. ^{[4
]}

Morancho, B. ^{[5
]}

Bruna, A. ^{[6
]}

Rueda, O. M. ^{[6
]}

Lai, Z. ^{[7
]}

Polanska, U. M. ^{[8
]}

Jones, G. N. ^{[8
]}

Kristel, P. ^{[9
]}

de Bustos, L. ^{[1
]}

Guzman, M. ^{[1
]}

Rodriguez, O. ^{[1
]}

Grueso, J. ^{[1
]}

Montalban, G. ^{[4
]}

Caratu, G. ^{[10
]}

Mancuso, F. ^{[10
]}

Fasani, R. ^{[11
]}

Jimenez, J. ^{[11
]}

Howat, W. J. ^{[8
]}

Dougherty, B. ^{[7
]}

Vivancos, A. ^{[10
]}

Nuciforo, P. ^{[11
]}

Serres-Creixams, X. ^{[12
]}

Rubio, I. T. ^{[13
]}

Oaknin, A. ^{[3
,14
]}

Cadogan, E. ^{[8
]}

Barrett, J. C. ^{[7
]}

Caldas, C. ^{[6
,15
,16
,17
]}

Baselga, J. ^{[18
,19
]}

Saura, C. ^{[3
,20
]}

Cortes, J. ^{[21
,22
]}

Arribas, J. ^{[5
,23
,24
,25
]}

Jonkers, J. ^{[10
]}

Diez, O. ^{[4
,26
]}

O'Connor, M. J. ^{[27
]}

Balmana, J. ^{[2
,3
]}

Serra, V ^{[1
,25
]}

机构：

[1] Vall dHebron Inst Oncol, Expt Therapeut Grp, Carrer Natzaret 115-117, Barcelona 08035, Spain

[2] Vall dHebron Inst Oncol, High Risk & Familial Canc, Barcelona, Spain

[3] Univ Autonoma Barcelona, Hosp Vall dHebron, Dept Med Oncol, Barcelona, Spain

[4] Vall dHebron Inst Oncol, Oncogenet Grp, Barcelona, Spain

[5] Vall dHebron Inst Oncol, Growth Factors Lab, Barcelona, Spain

[6] Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Cambridge, England

[7] AstraZeneca, Gatehouse Pk, Waltham, MA USA

[8] AstraZeneca, Canc Res UK Cambridge Inst, Oncol iMed, DNA Damage Response Biol Area, Cambridge, England

[9] Netherlands Canc Inst, Div Mol Pathol & Canc Genom, Amsterdam, Netherlands

[10] Vall dHebron Inst Oncol, Canc Genom Grp, Barcelona, Spain

[11] Vall dHebron Inst Oncol, Mol Oncol Grp, Barcelona, Spain

[12] Univ Autonoma Barcelona, Hosp Vall dHebron, Breast Canc Ctr, Dept Radiol, Barcelona, Spain

[13] Univ Autonoma Barcelona, Hosp Vall dHebron, Breast Canc Ctr, Breast Surg Unit, Barcelona, Spain

[14] Vall dHebron Inst Oncol, Gynecol Malignancies Grp, Barcelona, Spain

[15] Univ Cambridge, Li Ka Shing Ctr, Dept Oncol, Cambridge, England

[16] Cambridge Univ Hosp NHS Fdn Trust, NIHR Cambridge Biomed Res Ctr, Cambridge Breast Unit, Cambridge, England

[17] Cambridge Univ Hosp NHS Fdn Trust, Cambridge Expt Canc Med Ctr, Cambridge, England

[18] Mem Sloan Kettering Canc Ctr, HOPP, 1275 York Ave, New York, NY 10021 USA

[19] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA

[20] Vall dHebron Inst Oncol, Breast Canc & Melanoma Grp, Barcelona, Spain

[21] Ramon y Cajal Univ Hosp, Madrid, Spain

[22] Vall dHebron Inst Oncol, Barcelona, Spain

[23] Dept Biochem & Mol Biol, Bldg M,Campus UAB, Bellaterra, Cerdanyola Del, Spain

[24] ICREA, Barcelona, Spain

[25] CIBERONC, Barcelona, Spain

[26] Univ Autonoma Barcelona, Hosp Vall dHebron, Clin & Mol Genet Area, Barcelona, Spain

[27] AstraZeneca, Oncol Innovat Med & Early Dev Biotech Unit, DNA Damage Response Biol Area, Cambridge, England

来源：

ANNALS OF ONCOLOGY | 2018年 / 29卷 / 05期

基金：

欧盟地平线“2020”;

关键词：

germline BRCA; PARP inhibitor resistance; homologous recombination; RAD51; TP53BP1; ATM; FORK STABILITY; MUTANT-CELLS; OVARIAN; OLAPARIB; THERAPY; TUMORS; MUTATIONS; RESECTION; ATM;

D O I：

10.1093/annonc/mdy099

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Background: BRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity. Patients and methods: We investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/ 2-cancer patients treated with PARPi. Results: RAD51 nuclear foci, a surrogate marker of HRR functionality, were the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1-loss in 20% and RAD51-amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ataxia-telangiectasia mutated (ATM) inhibitor. Conclusion: Detection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors.

引用

页码：1203 / 1210

页数：8

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