American Association for Cancer Research
Browse

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

Download (317.49 kB)
journal contribution
posted on 2023-04-03, 21:20 authored by 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, Barry S. Taylor

PDF file - 321KB, A detailed description of additional methods utilized (and associated references) for sequencing and analysis as well as an explanatory note regarding the TM pathway in yeast.

History

ARTICLE 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. 988This article is highlighted in the In This Issue feature, p. 973

Usage metrics

    Cancer Discovery

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC