TY - JOUR AU - Bodo, Sahra AU - Campagne, Cécile AU - Thin, Tin Htwe AU - Higginson, Daniel S. AU - Vargas, H. Alberto AU - Hua, Guoqiang AU - Fuller, John D. AU - Ackerstaff, Ellen AU - Russell, James AU - Zhang, Zhigang AU - Klingler, Stefan AU - Cho, HyungJoon AU - Kaag, Matthew G. AU - Mazaheri, Yousef AU - Rimner, Andreas AU - Manova-Todorova, Katia AU - Epel, Boris AU - Zatcky, Joan AU - Cleary, Cristian R. AU - Rao, Shyam S. AU - Yamada, Yoshiya AU - Zelefsky, Michael J. AU - Halpern, Howard J. AU - Koutcher, Jason A. AU - Cordon-Cardo, Carlos AU - Greco, Carlo AU - Haimovitz-Friedman, Adriana AU - Sala, Evis AU - Powell, Simon N. AU - Kolesnick, Richard AU - Fuks, Zvi T1 - Single-dose radiotherapy disables tumor cell homologous recombination via ischemia/reperfusion injury PY - 2019/02/01/ AB - Tumor cure with conventional fractionated radiotherapy is 65%, dependent on tumor cell–autonomous gradual buildup of DNA double-strand break (DSB) misrepair. Here we report that single-dose radiotherapy (SDRT), a disruptive technique that ablates more than 90% of human cancers, operates a distinct dual-target mechanism, linking acid sphingomyelinase–mediated (ASMase-mediated) microvascular perfusion defects to DNA unrepair in tumor cells to confer tumor cell lethality. ASMase-mediated microcirculatory vasoconstriction after SDRT conferred an ischemic stress response within parenchymal tumor cells, with ROS triggering the evolutionarily conserved SUMO stress response, specifically depleting chromatin-associated free SUMO3. Whereas SUMO3, but not SUMO2, was indispensable for homology-directed repair (HDR) of DSBs, HDR loss of function after SDRT yielded DSB unrepair, chromosomal aberrations, and tumor clonogen demise. Vasoconstriction blockade with the endothelin-1 inhibitor BQ-123, or ROS scavenging after SDRT using peroxiredoxin-6 overexpression or the SOD mimetic tempol, prevented chromatin SUMO3 depletion, HDR loss of function, and SDRT tumor ablation. We also provide evidence of mouse-to-human translation of this biology in a randomized clinical trial, showing that 24 Gy SDRT, but not 3×9 Gy fractionation, coupled early tumor ischemia/reperfusion to human cancer ablation. The SDRT biology provides opportunities for mechanism-based selective tumor radiosensitization via accessing of SDRT/ASMase signaling, as current studies indicate that this pathway is tractable to pharmacologic intervention. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI97631 VL - 129 IS - 2 UR - https://doi.org/10.1172/JCI97631 SP - 786 EP - 801 PB - The American Society for Clinical Investigation ER -