@article{76377ef550174a21b72481e1c9ec9718,
title = "Inhibition of ATM induces hypersensitivity to proton irradiation by upregulating toxic end joining",
abstract = "Proton Bragg peak irradiation has a higher ionizing density than conventional photon irradiation or the entrance of the proton beam profile. Whether targeting the DNA damage response (DDR) could enhance vulnerability to the distinct pattern of damage induced by proton Bragg peak irradiation is currently unknown. Here, we performed genetic or pharmacologic manipulation of key DDR elements and evaluated DNA damage signaling, DNA repair, and tumor control in cell lines and xenografts treated with the same physical dose across a radiotherapy linear energy transfer spectrum. Radiotherapy consisted of 6 MV photons and the entrance beam or Bragg peak of a 76.8 MeV spot scanning proton beam. More complex DNA double-strand breaks (DSB) induced by Bragg peak proton irradiation preferentially underwent resection and engaged homologous recombination (HR) machinery. Unexpectedly, the ataxia-telangiectasia mutated (ATM) inhibitor, AZD0156, but not an inhibitor of ATM and Rad3-related, rendered cells hypersensitive to more densely ionizing proton Bragg peak irradiation. ATM inhibition blocked resection and shunted more DSBs to processing by toxic ligation through nonhomologous end-joining, whereas loss of DNA ligation via XRCC4 or Lig4 knockdown rescued resection and abolished the enhanced Bragg peak cell killing. Proton Bragg peak monotherapy selectively sensitized cell lines and tumor xenografts with inherent HR defects, and the repair defect induced by ATM inhibitor coadministration showed enhanced efficacy in HR-proficient models. In summary, inherent defects in HR or administration of an ATM inhibitor in HR-proficient tumors selectively enhances the relative biological effectiveness of proton Bragg peak irradiation.",
author = "Qin Zhou and Howard, {Michelle E.} and Xinyi Tu and Qian Zhu and Denbeigh, {Janet M.} and Remmes, {Nicholas B.} and Herman, {Michael G.} and Beltran, {Chris J.} and Jian Yuan and Greipp, {Patricia T.} and Boughey, {Judy C.} and Liewei Wang and Neil Johnson and Goetz, {Matthew P.} and Sarkaria, {Jann N.} and Zhenkun Lou and Mutter, {Robert W.}",
note = "Funding Information: The authors would like to acknowledge AstraZeneca for provision of pharmaceutical agents and Stephen Durant for scientific input and dosing recommendations. The authors would also like to acknowledge Ann C. Tuma, Gasper J. Kitange, Katrina K. Bakken, Danielle Burgenske, Brett L. Carlson, Mark A. Schroeder, and Shiv K. Gupta for their assistance with experimental techniques, and radiation therapists Courtney Vinsand, Jill Frericks, Adam Boyer, Brooke Tebo, Alex Kehren, Tracy Gadient, Mackenzie Breedon, Jaimee Sullivan, Nicole Johnson, Rashad Momoh, and Kristen Dezell for their assistance with proton irradiation. This work was supported, in part, by R01 CA203561 (to Z. Lou) and the American Society for Radiation Oncology, the NCI of the NIH under award number P50CA116201, the Mayo Clinic Research Pipeline K2R Award, and K12 HD065987 (to R.W. Mutter). Funding Information: M.E. Howard reports grants from Radiation Research Society during the conduct of the study and Particle Therapy Co-Operative Group outside the submitted work. J.C. Boughey reports grants from Eli Lilly outside the submitted work. M.P. Goetz reports other support from Eagle Pharmaceuticals, Lilly, Biovica, Novartis, Sermonix, Context Pharm, Pfizer, and BioTheranostics and grants from Pfizer, Sermonix, and Lilly outside the submitted work. J.N. Sarkaria reports grants from Novartis, Basilea, Genentech, Sanofi, BeiGene, Lilly, GlaxoSmithKline, Peloton, Glionova, Bristol Myers Squibb, Cavion, Curtana, Forma, AbbVie, Actuate, Boehringer Ingelheim, Bayer, Celgene, Cible, Mitochon, Wayshine, and Nerviano Medical Sciences outside the submitted work. Z. Lou reports grants from NIH during the conduct of the study. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",
year = "2021",
month = jun,
doi = "10.1158/0008-5472.CAN-20-2960",
language = "English (US)",
volume = "81",
pages = "3333--3346",
journal = "Cancer research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "12",
}