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Zhou Q , Howard ME , Tu X , Zhu Q , Denbeigh JM , Remmes NB , Herman MG , Beltran CJ , Yuan J , Greipp PT , Boughey JC , Wang L , Johnson N , Goetz MP , Sarkaria JN , Lou Z , Mutter RW
Inhibition of ATM induces hypersensitivity to proton irradiation by upregulating toxic end joining
Cancer Res. 2021 Feb 17;81(12) :3333-3346
PMID: 33597272    PMCID: PMC8260463    URL: https://www.ncbi.nlm.nih.gov/pubmed/33597272
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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 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 DNA damage response 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 induced by Bragg peak proton irradiation preferentially underwent resection and engaged homologous recombination (HR) machinery. Unexpectedly, the ATM inhibitor AZD0156 but not an inhibitor of ATR rendered cells hypersensitive to more densely ionizing proton Bragg peak irradiation. ATM inhibition blocked resection and shunted more double strand breaks 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 co-administration showed enhanced efficacy in HR proficient models. In summary, inherent defects in HR or administration of an ATM inhibitor in HR proficient tumors selectively enhance the relative biological effectiveness of proton Bragg peak irradiation.
1538-7445 Zhou, Qin Howard, Michelle E Orcid: 0000-0001-9870-9218 Tu, Xinyi Zhu, Qian Denbeigh, Janet M Remmes, Nicholas B Herman, Michael G Beltran, Chris J Yuan, Jian Greipp, Patricia T Boughey, Judy C Orcid: 0000-0003-3820-3228 Wang, Liewei Johnson, Neil Goetz, Matthew P Sarkaria, Jann N Lou, Zhenkun Mutter, Robert W R01 CA214799/CA/NCI NIH HHS/United States Journal Article United States Cancer Res. 2021 Feb 17:canres.CAN-20-2960-A.2020. doi: 10.1158/0008-5472.CAN-20-2960.