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.
Sahra Bodo, Cécile Campagne, Tin Htwe Thin, Daniel S. Higginson, H. Alberto Vargas, Guoqiang Hua, John D. Fuller, Ellen Ackerstaff, James Russell, Zhigang Zhang, Stefan Klingler, HyungJoon Cho, Matthew G. Kaag, Yousef Mazaheri, Andreas Rimner, Katia Manova-Todorova, Boris Epel, Joan Zatcky, Cristian R. Cleary, Shyam S. Rao, Yoshiya Yamada, Michael J. Zelefsky, Howard J. Halpern, Jason A. Koutcher, Carlos Cordon-Cardo, Carlo Greco, Adriana Haimovitz-Friedman, Evis Sala, Simon N. Powell, Richard Kolesnick, Zvi Fuks
SUMO3, not SUMO2, is required for conjugation-dependent activation of HDR mediators.