Mechanisms of Therapy Resistance in Patient-Derived Xenograft Models of BRCA1-Deficient Breast Cancer

Brugge, Petra ter; Kristel, Petra; Burg, Eline van der; Boon, Ute; Maaker, Michiel de; Lips, Esther H.; Mulder, Lennart; Ruiter, Julian de; Moutinho, Cátia; Gevensleben, Heidrun; Marangoni, Elisabetta; Majewski, Ian J.; Jóźwiak, Katarzyna; Kloosterman, Wigard P.; Roosmalen, Markus van; Duran, Karen; Hogervorst, Frans B.L.; Turner, Nicholas C.; Esteller, Manel; Cuppen, Edwin; Wesseling, Jelle; Jonkers, Jos

doi:10.1093/jnci/djw148

Cited by 176 publications

(159 citation statements)

References 43 publications

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“…A potential limitation of these approaches is the lack of specificity in HRR‐altered tumors that have restored the HRR function (Watkins et al , ; Konstantinopoulos et al , ). Other approaches entail the quantification of BRCA1 promoter hypermethylation, BRCA1 mRNA expression, or the detection of the HRR protein RAD51 forming nuclear foci after DNA damage, as surrogate of HRR functionality (Graeser et al , ; Naipal et al , ; ter Brugge et al , ). In these sense, we showed that, in gBRCA tumors, RAD51 foci could be detected in untreated samples and correlated with PARPi resistance regardless of the underlying mechanism restoring HRR function (Cruz et al , ).…”

Section: Introductionmentioning

confidence: 99%

A RAD 51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation

Castroviejo-Bermejo¹,

et al. 2018

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Poly(ADP‐ribose) polymerase (PARP) inhibitors (PARPi) are effective in cancers with defective homologous recombination DNA repair (HRR), including BRCA1/2‐related cancers. A test to identify additional HRR‐deficient tumors will help to extend their use in new indications. We evaluated the activity of the PARPi olaparib in patient‐derived tumor xenografts (PDXs) from breast cancer (BC) patients and investigated mechanisms of sensitivity through exome sequencing, BRCA1 promoter methylation analysis, and immunostaining of HRR proteins, including RAD51 nuclear foci. In an independent BC PDX panel, the predictive capacity of the RAD51 score and the homologous recombination deficiency (HRD) score were compared. To examine the clinical feasibility of the RAD51 assay, we scored archival breast tumor samples, including PALB2‐related hereditary cancers. The RAD51 score was highly discriminative of PARPi sensitivity versus PARPi resistance in BC PDXs and outperformed the genomic test. In clinical samples, all PALB2‐related tumors were classified as HRR‐deficient by the RAD51 score. The functional biomarker RAD51 enables the identification of PARPi‐sensitive BC and broadens the population who may benefit from this therapy beyond BRCA1/2‐related cancers.

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Section: Introductionmentioning

confidence: 99%

A RAD 51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation

Castroviejo-Bermejo¹,

et al. 2018

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“…Evidence has shown that PDXs retain the genome-wide exomic nucleotide variants, gene copy number alterations, and DNA methylation patterns of their corresponding tumors [1][2][3][4] irrespective of the number of passages, 1,3 although clonal selection during initial engraftment and passaging of PDXs has been observed. 4 PDX models also are increasingly used in the mechanistic characterization of resistance to targeted therapies, [9][10][11] the identification of novel Cancer November 1, 2019 biomarkers 12 and therapeutic targets, 13 and the characterization of intratumoral heterogeneity. 7,8 An analysis of the treatment responses of PDXs established from 92 patients with different solid tumors demonstrated a significant association between drug response in patients and the response in mice bearing the corresponding PDXs, indicating that PDXs can predict clinical treatment response.…”

Section: Introductionmentioning

confidence: 99%

Tumor characteristics associated with engraftment of patient‐derived non–small cell lung cancer xenografts in immunocompromised mice

Chen

Zhang

Wang

et al. 2019

Cancer

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BACKGROUND: Patient-derived xenograft (PDX) models increasingly are used in translational research. However, the engraftment rates of patient tumor samples in immunodeficient mice to PDX models vary greatly. METHODS: Tumor tissue samples from 308 patients with non-small cell lung cancer were implanted in immunodeficient mice. The patients were followed for 1.5 to approximately 6 years. The authors performed histological analysis of PDXs and some residual tumor tissues in mice with failed PDX growth at 1 year after implantation. Quantitative polymerase chain reaction and enzyme-linked immunoadsorbent assay were performed to measure the levels of Epstein-Barr virus genes and human immunoglobulin G in PDX samples. Patient characteristics were compared for PDX growth and overall survival as outcomes using Cox regression analyses. Disease staging was based on the 7th TNM staging system. RESULTS:The overall engraftment rate for PDXs from patients with non-small cell lung cancer was 34%. Squamous cell carcinomas had a higher engraftment rate (53%) compared with adenocarcinomas. Tumor samples from patients with stage II and stage III disease and from larger tumors were found to have relatively high engraftment rates. Patients whose tumors successfully engrafted had worse overall survival, particularly those individuals with adenocarcinoma, stage III or stage IV disease, and moderately differentiated tumors. Lymphoma formation was one of the factors associated with engraftment failure. Human CD8-positive and CD20-positive cells were detected in residual samples of tumor tissue that failed to generate a PDX at 1 year after implantation. Human immunoglobulin G was detected in the plasma of mice that did not have PDX growth at 14 months after implantation. CONCLUSIONS: The results of the current study indicate that the characteristics of cancer cells and the tumor immune microenvironment in primary tumors both can affect engraftment of a primary tumor sample. Cancer 2019;125:3738-3748.

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“…In an in vitro setting it was found that BRCA1 promoter methylation in the wild-type UACC3199 breast cancer cell line was equally sensitive to PARP inhibition as the BRCA1 mutant MDA-MB-436 line (49). In addition, a patient-derived xenograft model confirmed the presence of BRCA1 methylation in a subset of tumors, and that loss of methylation was associated with PARP inhibitor resistance in this context (50). These data hint at a possible epigenetic role in determining likely sensitivity to PARP inhibitors that could be used in treating patients with breast or ovarian cancer.…”

Section: Epigenetic Predictive Biomarkersmentioning

confidence: 86%

Epigenetics and Precision Oncology

2017

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Epigenetic alterations such as DNA methylation defects and aberrant covalent histone modifications occur within all cancers and are selected for throughout the natural history of tumor formation with changes being detectable in early onset, progression and, ultimately, recurrence and metastasis. The ascertainment and use of these marks to identify at-risk patient populations, refine diagnostic criteria, and provide prognostic and predictive factors to guide treatment decisions is of growing clinical relevance. Further, the targetable nature of epigenetic modifications provides a unique opportunity to alter treatment paradigms and provide new therapeutic options for patients whose malignancies possess these aberrant epigenetic modifications, paving the way for new and personalized medicine. DNA methylation has proven to be of significant clinical utility for its stability and relative ease of testing. The intent of this review is to elaborate upon well-supported examples of epigenetic precision medicine and how the field is moving forward, primarily in the context of aberrant DNA methylation.

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Mechanisms of Therapy Resistance in Patient-Derived Xenograft Models of BRCA1-Deficient Breast Cancer

Cited by 176 publications

References 43 publications

A RAD 51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation

A RAD 51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation

Tumor characteristics associated with engraftment of patient‐derived non–small cell lung cancer xenografts in immunocompromised mice

Epigenetics and Precision Oncology

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