Single-dose radiotherapy disables tumor cell homologous recombination via ischemia/reperfusion injury Journal Article

Authors: Bodo, S.; Campagne, C.; Thin, T. H.; Higginson, D. S.; Vargas, H. A.; Hua, G.; Fuller, J. D.; Ackerstaff, E.; Russell, J.; Zhang, Z.; Klingler, S.; Cho, H.; Kaag, M. G.; Mazaheri, Y.; Rimner, A.; Manova-Todorova, K.; Epel, B.; Zatcky, J.; Cleary, C. R.; Rao, S. S.; Yamada, Y.; Zelefsky, M. J.; Halpern, H. J.; Koutcher, J. A.; Cordon-Cardo, C.; Greco, C.; Haimovitz-Friedman, A.; Sala, E.; Powell, S. N.; Kolesnick, R.; Fuks, Z.
Article Title: Single-dose radiotherapy disables tumor cell homologous recombination via ischemia/reperfusion injury
Abstract: 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.
Journal Title: Journal of Clinical Investigation
Volume: 129
Issue: 2
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 2019-02-01
Start Page: 786
End Page: 801
Language: English
DOI: 10.1172/jci97631
PUBMED: 30480549
PROVIDER: scopus
PMCID: PMC6355243
Notes: Article -- Export Date: 1 March 2019 -- Source: Scopus
Altmetric Score