RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer
| Autor: | Ana Vivancos, Petra Kristel, Ginevra Caratu, Isabel T. Rubio, Ana Oaknin, Orland Diez, J. Jimenez, Gemma N Jones, L. de Bustos, J. Cortés, J.C. Barrett, Alejandra Bruna, Urszula M. Polanska, Marta Castroviejo-Bermejo, Beatriz Morancho, Carlos Caldas, Gemma Montalban, Yasir H. Ibrahim, Xavier Serres-Créixams, Sandra Bonache, Judit Grueso, Cristina Cruz, Francesco M. Mancuso, Paolo Nuciforo, Joaquín Arribas, Elaine Cadogan, Mario Guzmán, William J. Howat, Alba Llop-Guevara, Judith Balmaña, Sara Gutiérrez-Enríquez, Roberta Fasani, Brian Dougherty, Jos Jonkers, Zhongwu Lai, J. Baselga, Olga Rodriguez, Mark J. O'Connor, Violeta Serra, Albert Gris-Oliver, Oscar M. Rueda, Cristina Saura |
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| Přispěvatelé: | Bruna, Alejandra [0000-0003-1214-9665], Caldas, Carlos [0000-0003-3547-1489], Apollo - University of Cambridge Repository |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
endocrine system diseases RAD51 homologous recombination Poly (ADP-Ribose) Polymerase Inhibitor Mice chemistry.chemical_compound 0302 clinical medicine Breast Tumors Medicine Breast skin and connective tissue diseases Exome sequencing BRCA1 Protein Hematology 3. Good health Treatment Outcome Germline BRCA Oncology germline BRCA 030220 oncology & carcinogenesis PARP inhibitor Biomarker (medicine) Female TP53BP1 DNA damage Mice Nude Breast Neoplasms Poly(ADP-ribose) Polymerase Inhibitors Olaparib 03 medical and health sciences Germline mutation Biomarkers Tumor Animals Humans Homologous recombination Germ-Line Mutation Retrospective Studies BRCA2 Protein business.industry Recombinational DNA Repair Original Articles Xenograft Model Antitumor Assays 030104 developmental biology chemistry Drug Resistance Neoplasm ATM PARP inhibitor resistance Cancer research Rad51 Recombinase business |
| Zdroj: | Annals of Oncology Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid Consejería de Sanidad de la Comunidad de Madrid |
| ISSN: | 0923-7534 |
| DOI: | 10.1093/annonc/mdy099 |
| Popis: | 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 En el cas dels drets, per a usos comercials contactar amb: journals.permissions@oup.com 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. |
| Databáze: | OpenAIRE |
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