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Clin Cancer Res. 2019 Feb 1;25(3):977-988. doi: 10.1158/1078-0432.CCR-18-1001. Epub 2018 Jul 6.

ERCC2 Helicase Domain Mutations Confer Nucleotide Excision Repair Deficiency and Drive Cisplatin Sensitivity in Muscle-Invasive Bladder Cancer.

Author information

1
Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, New York. kent_mouw@dfci.harvard.edu iyerg@mskcc.org.
2
Department of Urology, Roswell Park Cancer Institute, Buffalo, New York.
3
Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
5
Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
6
Cancer Center, Massachusetts General Hospital, Boston, Massachusetts.
7
Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, Massachusetts.
8
Drug Discovery, Bayer AG, Berlin, Germany.
9
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
10
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
11
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
12
Department of Urology, Einstein Medical Center, Philadelphia, Pennsylvania.
13
Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
14
Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
15
Weill Cornell Medical College, Cornell University, New York, New York.
16
Ludwig Center at Harvard, Boston, Massachusetts.
17
Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. kent_mouw@dfci.harvard.edu iyerg@mskcc.org.
18
Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts. kent_mouw@dfci.harvard.edu iyerg@mskcc.org.

Abstract

PURPOSE:

DNA-damaging agents comprise the backbone of systemic treatment for many tumor types; however, few reliable predictive biomarkers are available to guide use of these agents. In muscle-invasive bladder cancer (MIBC), cisplatin-based chemotherapy improves survival, yet response varies widely among patients. Here, we sought to define the role of the nucleotide excision repair (NER) gene ERCC2 as a biomarker predictive of response to cisplatin in MIBC.

EXPERIMENTAL DESIGN:

Somatic missense mutations in ERCC2 are associated with improved response to cisplatin-based chemotherapy; however, clinically identified ERCC2 mutations are distributed throughout the gene, and the impact of individual ERCC2 variants on NER capacity and cisplatin sensitivity is unknown. We developed a microscopy-based NER assay to profile ERCC2 mutations observed retrospectively in prior studies and prospectively within the context of an institution-wide tumor profiling initiative. In addition, we created the first ERCC2-deficient bladder cancer preclinical model for studying the impact of ERCC2 loss of function.

RESULTS:

We used our functional assay to test the NER capacity of clinically observed ERCC2 mutations and found that most ERCC2 helicase domain mutations cannot support NER. Furthermore, we show that introducing an ERCC2 mutation into a bladder cancer cell line abrogates NER activity and is sufficient to drive cisplatin sensitivity in an orthotopic xenograft model.

CONCLUSIONS:

Our data support a direct role for ERCC2 mutations in driving cisplatin response, define the functional landscape of ERCC2 mutations in bladder cancer, and provide an opportunity to apply combined genomic and functional approaches to prospectively guide therapy decisions in bladder cancer.See related commentary by Grivas, p. 907.

PMID:
29980530
PMCID:
PMC6434536
[Available on 2020-02-01]
DOI:
10.1158/1078-0432.CCR-18-1001

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