RT Journal Article
SR Electronic
T1 Synthetic Lethality in ATM-Deficient <em>RAD50</em>-Mutant Tumors Underlies Outlier Response to Cancer Therapy
JF Cancer Discovery
JO CANCER DISCOVERY
FD American Association for Cancer Research
SP 1014
OP 1021
DO 10.1158/2159-8290.CD-14-0380
VO 4
IS 9
A1 Al-Ahmadie, Hikmat
A1 Iyer, Gopa
A1 Hohl, Marcel
A1 Asthana, Saurabh
A1 Inagaki, Akiko
A1 Schultz, Nikolaus
A1 Hanrahan, Aphrothiti J.
A1 Scott, Sasinya N.
A1 Brannon, A. Rose
A1 McDermott, Gregory C.
A1 Pirun, Mono
A1 Ostrovnaya, Irina
A1 Kim, Philip
A1 Socci, Nicholas D.
A1 Viale, Agnes
A1 Schwartz, Gary K.
A1 Reuter, Victor
A1 Bochner, Bernard H.
A1 Rosenberg, Jonathan E.
A1 Bajorin, Dean F.
A1 Berger, Michael F.
A1 Petrini, John H.J.
A1 Solit, David B.
A1 Taylor, Barry S.
YR 2014
UL http://cancerdiscovery.aacrjournals.org/content/4/9/1014.abstract
AB 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