RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer
Cruz, C. (Vall d'Hebron Institut d'Oncologia)
Castroviejo-Bermejo, Marta (Experimental Therapeutics Group)
Gutiérrez-Enríquez, Sara (Oncogenetics Group)
Llop-Guevara, A. (Experimental Therapeutics Group)
Ibrahim, Y. H. (Experimental Therapeutics Group)
Gris-Oliver, Albert. (Experimental Therapeutics Group)
Bonache, Sandra (Oncogenetics Group)
Morancho, Beatriz (Vall d'Hebron Institut d'Oncologia)
Bruna, Alejandra (Cancer Research UK Cambridge Institute. University of Cambridge)
Rueda, O. M. (Cancer Research UK Cambridge Institute. University of Cambridge)
Lai, Z. (AstraZeneca (USA))
Polanska, U. M. (Cancer Research UK. Cambridge Institute)
Jones, G. N. (Cancer Research UK. Cambridge Institute)
Kristel, P. (The Netherlands Cancer Institute (Amsterdam, Països Baixos))
de Bustos, L. (Experimental Therapeutics Group)
Guzmán, Marta (Experimental Therapeutics Group)
Rodríguez, O. (Experimental Therapeutics Group)
Grueso, Judit (Experimental Therapeutics Group)
Montalban, G. (Oncogenetics Group)
Caratù, Ginevra (Cancer Genomics Group)
Mancuso, Francesco M (Cancer Genomics Group)
Fasani, R. (Vall d'Hebron Institut d'Oncologia)
Jiménez, J. (Vall d'Hebron Institut d'Oncologia)
Howat, W. J. (Cancer Research UK. Cambridge Institute)
Dougherty, B. (AstraZeneca (USA))
Vivancos, A. (Cancer Genomics Group)
Nuciforo, Paolo (Vall d'Hebron Institut d'Oncologia)
Serres-Créixams, X. (Department of Radiology)
Rubio Rodríguez, Isabel Teresa (Hospital Universitari Vall d'Hebron)
Oaknin, Ana (Vall d'Hebron Institut d'Oncologia)
Cadogan, E. (Cancer Research UK. Cambridge Institute)
Barrett, J. Carl (AstraZeneca (USA))
Caldas, Carlos (NIHR Cambridge Biomedical Research Centre (Regne Unit))
Baselga Torres, Josep, 1959-2021, (Memorial Sloan Kettering Cancer Center)
Saura, Cristina (Vall d'Hebron Institut d'Oncologia)
Cortés, Javier (Vall d'Hebron Institut d'Oncologia)
Arribas, Joaquín V (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Jonkers, Jos (Cancer Genomics Group)
Diez, Orland (Hospital Universitari Vall d'Hebron)
O'Connor, M. J. (Oncology Innovative Medicine and Early Development Biotech Unit. AstraZeneca (UK))
Balmaña Gelpí, Judith (Vall d'Hebron Institut d'Oncologia)
Serra, Violeta (Vall d'Hebron Institut d'Oncologia)

Date:	2018
Abstract:	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. 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. 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. 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.
Grants:	Instituto de Salud Carlos III FIS/PI17/01080 Instituto de Salud Carlos III FIS/PI12-02606 Instituto de Salud Carlos III FIS/PI15-00355 Instituto de Salud Carlos III FIS/PI13-01711 Instituto de Salud Carlos III CP14-00228 Instituto de Salud Carlos III CP10-00617 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014/SGR-1331 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-540
Note:	Altres ajuts: European Research Area-NET, Transcan-2 (AC15/00063), Asociación Española Contra el Cáncer (LABAE16020PORTT) i AIOC15152806CRUZ, Generalitat de Catalunya(PERIS, SLT002/16/00477
Note:	En el cas dels drets, per a usos comercials contactar amb: journals.permissions@oup.com
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Germline BRCA ; PARP inhibitor resistance ; Homologous recombination ; RAD51 ; TP53BP1 ; ATM
Published in:	Annals of oncology, Vol. 29, Issue 5 (May 2018) , p. 1203-1210, ISSN 1569-8041

DOI: 10.1093/annonc/mdy099
PMID: 29635390

8 p, 473.7 KB

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