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Synthetic lethality in ATM-deficient RAD50-mutant tumors underlies outlier response to cancer therapy.

Cancer discovery (2014-06-18)
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

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. 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.

Product Number
Product Description

Trichloroacetic acid, ACS reagent, ≥99.0%
Trichloroacetic acid solution, 6.1 N
Trichloroacetic acid, BioXtra, ≥99.0%
Trichloroacetic acid, ≥99.0% (titration)
Trichloroacetic acid, BioUltra, ≥99.5% (T)
Trichloroacetic acid, suitable for electrophoresis, suitable for fixing solution (for IEF and PAGE gels), ≥99%
Trichloroacetic acid, ACS reagent, for the determination of Fe in blood according to Heilmeyer, ≥99.5%
Anti-RAD50 antibody produced in rabbit, affinity isolated antibody, ammonium sulfate suspension
Rabbit anti-Rad50 Antibody, Affinity Purified, Powered by Bethyl Laboratories, Inc.