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

Although BRCA1-deficient tumors are extremely sensitive to DNA-damaging drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, recurrences do occur and, consequently, resistance to therapy remains a serious clinical problem. To study the underlying mechanisms, we induced therapy resistance in pati...

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Veröffentlicht in:JNCI : Journal of the National Cancer Institute Jg. 108; H. 11
Hauptverfasser: Ter Brugge, Petra, Kristel, Petra, van der Burg, Eline, Boon, Ute, de Maaker, Michiel, Lips, Esther, Mulder, Lennart, de Ruiter, Julian, Moutinho, Catia, Gevensleben, Heidrun, Marangoni, Elisabetta, Majewski, Ian, Józwiak, Katarzyna, Kloosterman, Wigard, van Roosmalen, Markus, Duran, Karen, Hogervorst, Frans, Turner, Nick, Esteller, Manel, Cuppen, Edwin, Wesseling, Jelle, Jonkers, Jos
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.11.2016
Schlagworte:
Animals
Antineoplastic Agents - therapeutic use
BRCA1 Protein - deficiency
Cisplatin - therapeutic use
DNA Methylation
Drug Resistance, Neoplasm - genetics
Female
Gene Expression
Gene Fusion
Genes, BRCA1
Humans
Melphalan - therapeutic use
Mice
Mutation
Neoplasm Transplantation
Nimustine - therapeutic use
Phthalazines - therapeutic use
Piperazines - therapeutic use
Promoter Regions, Genetic
Triple Negative Breast Neoplasms - drug therapy
Triple Negative Breast Neoplasms - genetics
ISSN:1460-2105
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Zusammenfassung:Although BRCA1-deficient tumors are extremely sensitive to DNA-damaging drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, recurrences do occur and, consequently, resistance to therapy remains a serious clinical problem. To study the underlying mechanisms, we induced therapy resistance in patient-derived xenograft (PDX) models of BRCA1-mutated and BRCA1-methylated triple-negative breast cancer. A cohort of 75 mice carrying BRCA1-deficient breast PDX tumors was treated with cisplatin, melphalan, nimustine, or olaparib, and treatment sensitivity was determined. In tumors that acquired therapy resistance, BRCA1 expression was investigated using quantitative real-time polymerase chain reaction and immunoblotting. Next-generation sequencing, methylation-specific multiplex ligation-dependent probe amplification (MLPA) and Target Locus Amplification (TLA)-based sequencing were used to determine mechanisms of BRCA1 re-expression in therapy-resistant tumors. BRCA1 protein was not detected in therapy-sensitive tumors but was found in 31 out of 42 resistant cases. Apart from previously described mechanisms involving BRCA1-intragenic deletions and loss of BRCA1 promoter hypermethylation, a novel resistance mechanism was identified in four out of seven BRCA1-methylated PDX tumors that re-expressed BRCA1 but retained BRCA1 promoter hypermethylation. In these tumors, we found de novo gene fusions that placed BRCA1 under the transcriptional control of a heterologous promoter, resulting in re-expression of BRCA1 and acquisition of therapy resistance. In addition to previously described clinically relevant resistance mechanisms in BRCA1-deficient tumors, we describe a novel resistance mechanism in BRCA1-methylated PDX tumors involving de novo rearrangements at the BRCA1 locus, demonstrating that BRCA1-methylated breast cancers may acquire therapy resistance via both epigenetic and genetic mechanisms.
Bibliographie:ObjectType-Article-1
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ISSN:1460-2105
DOI:10.1093/jnci/djw148