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Synthetic Lethality in ATM-Deficient RAD50-Mutant Tumors Underlies Outlier Response to Cancer Therapy

Hikmat Al-Ahmadie, Gopa Iyer, Marcel Hohl, Saurabh Asthana, Akiko Inagaki, Nikolaus Schultz, Aphrothiti J. Hanrahan, Sasinya N. Scott, A. Rose Brannon, Gregory C. McDermott, Mono Pirun, Irina Ostrovnaya, Philip Kim, Nicholas D. Socci, Agnes Viale, Gary K. Schwartz, Victor Reuter, Bernard H. Bochner, Jonathan E. Rosenberg, Dean F. Bajorin, Michael F. Berger, John H.J. Petrini, David B. Solit and Barry S. Taylor
Hikmat Al-Ahmadie
1Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Gopa Iyer
2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
4Department of Medicine, Weill Cornell Medical College, New York, New York.
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Marcel Hohl
5Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Saurabh Asthana
6Department of Medicine, University of California, San Francisco, California.
7Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
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Akiko Inagaki
5Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Nikolaus Schultz
8Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Aphrothiti J. Hanrahan
3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Sasinya N. Scott
1Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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A. Rose Brannon
1Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Gregory C. McDermott
1Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Mono Pirun
9Bioinformatics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York.
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Irina Ostrovnaya
10Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Philip Kim
3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
11Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
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Nicholas D. Socci
9Bioinformatics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York.
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Agnes Viale
12Genomics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York.
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Gary K. Schwartz
2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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Victor Reuter
1Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Bernard H. Bochner
11Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
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Jonathan E. Rosenberg
2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
4Department of Medicine, Weill Cornell Medical College, New York, New York.
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Dean F. Bajorin
2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
4Department of Medicine, Weill Cornell Medical College, New York, New York.
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Michael F. Berger
1Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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John H.J. Petrini
5Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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  • For correspondence: taylorb@mskcc.org petrinij@mskcc.org solitd@mskcc.org
David B. Solit
2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
4Department of Medicine, Weill Cornell Medical College, New York, New York.
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  • For correspondence: taylorb@mskcc.org petrinij@mskcc.org solitd@mskcc.org
Barry S. Taylor
6Department of Medicine, University of California, San Francisco, California.
7Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
13Department of Epidemiology and Biostatistics, University of California, San Francisco, California.
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  • For correspondence: taylorb@mskcc.org petrinij@mskcc.org solitd@mskcc.org
DOI: 10.1158/2159-8290.CD-14-0380 Published September 2014
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Abstract

Metastatic solid tumors are almost invariably fatal. Patients with disseminated small-cell cancers have a particularly unfavorable prognosis, with most succumbing to their disease within two years. Here, we report on the genetic and functional analysis of an outlier curative response of a patient with metastatic small-cell cancer to combined checkpoint kinase 1 (CHK1) inhibition and DNA-damaging chemotherapy. Whole-genome sequencing revealed a clonal hemizygous mutation in the Mre11 complex gene RAD50 that attenuated ATM signaling which in the context of CHK1 inhibition contributed, via synthetic lethality, to extreme sensitivity to irinotecan. As Mre11 mutations occur in a diversity of human tumors, the results suggest a tumor-specific combination therapy strategy in which checkpoint inhibition in combination with DNA-damaging chemotherapy is synthetically lethal in tumor cells but not normal cells with somatic mutations that impair Mre11 complex function.

Significance: Strategies to effect deep and lasting responses to cancer therapy in patients with metastatic disease have remained difficult to attain, especially in early-phase clinical trials. Here, we present an in-depth genomic and functional genetic analysis identifying RAD50 hypomorphism as a contributing factor to a curative response to systemic combination therapy in a patient with recurrent, metastatic small-cell cancer. Cancer Discov; 4(9); 1014–21. ©2014 AACR.

See related commentary by Peng et al., p. 988

This article is highlighted in the In This Issue feature, p. 973

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Received April 10, 2014.
  • Revision received June 4, 2014.
  • Accepted June 11, 2014.
  • ©2014 American Association for Cancer Research.
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Cancer Discovery: 4 (9)
September 2014
Volume 4, Issue 9
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Synthetic Lethality in ATM-Deficient RAD50-Mutant Tumors Underlies Outlier Response to Cancer Therapy
Hikmat Al-Ahmadie, Gopa Iyer, Marcel Hohl, Saurabh Asthana, Akiko Inagaki, Nikolaus Schultz, Aphrothiti J. Hanrahan, Sasinya N. Scott, A. Rose Brannon, Gregory C. McDermott, Mono Pirun, Irina Ostrovnaya, Philip Kim, Nicholas D. Socci, Agnes Viale, Gary K. Schwartz, Victor Reuter, Bernard H. Bochner, Jonathan E. Rosenberg, Dean F. Bajorin, Michael F. Berger, John H.J. Petrini, David B. Solit and Barry S. Taylor
Cancer Discov September 1 2014 (4) (9) 1014-1021; DOI: 10.1158/2159-8290.CD-14-0380

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Synthetic Lethality in ATM-Deficient RAD50-Mutant Tumors Underlies Outlier Response to Cancer Therapy
Hikmat Al-Ahmadie, Gopa Iyer, Marcel Hohl, Saurabh Asthana, Akiko Inagaki, Nikolaus Schultz, Aphrothiti J. Hanrahan, Sasinya N. Scott, A. Rose Brannon, Gregory C. McDermott, Mono Pirun, Irina Ostrovnaya, Philip Kim, Nicholas D. Socci, Agnes Viale, Gary K. Schwartz, Victor Reuter, Bernard H. Bochner, Jonathan E. Rosenberg, Dean F. Bajorin, Michael F. Berger, John H.J. Petrini, David B. Solit and Barry S. Taylor
Cancer Discov September 1 2014 (4) (9) 1014-1021; DOI: 10.1158/2159-8290.CD-14-0380
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