Synthetic lethality in ATM-deficient RAD50-mutant tumors underlies outlier response to cancer therapy Journal Article
| Authors: | Al-Ahmadie, H.; Iyer, G.; Hohl, M.; Asthana, S.; Inagaki, A.; Schultz, N.; Hanrahan, A. J.; Scott, S. N.; Brannon, A. R.; McDermott, G. C.; Pirun, M.; Ostrovnaya, I.; Kim, P.; Socci, N. D.; Viale, A.; Schwartz, G. K.; Reuter, V.; Bochner, B. H.; Rosenberg, J. E.; Bajorin, D. F.; Berger, M. F.; Petrini, J. H. J.; Solit, D. B.; Taylor, B. S. |
| Article Title: | Synthetic lethality in ATM-deficient RAD50-mutant tumors underlies outlier response to cancer therapy |
| 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. © 2014 American Association for Cancer Research. |
| Journal Title: | Cancer Discovery |
| Volume: | 4 |
| Issue: | 9 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2014-09-01 |
| Start Page: | 1014 |
| End Page: | 1021 |
| Language: | English |
| DOI: | 10.1158/2159-8290.cd-14-0380 |
| PROVIDER: | scopus |
| PMCID: | PMC4155059 |
| PUBMED: | 24934408 |
| DOI/URL: | |
| Notes: | Export Date: 1 October 2014 -- Source: Scopus |
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