Journal article
Inhibition of ATM Induces Hypersensitivity to Proton Irradiation by Upregulating Toxic End Joining
Cancer research (Chicago, Ill.), Vol.81(12), pp.3333-3346
06/15/2021
DOI: 10.1158/0008-5472.CAN-20-2960
PMCID: PMC8260463
PMID: 33597272
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 xenogra Its 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.
Significance: Coadministration of an ATM inhibitor rewires DNA repair machinery to render cancer cells uniquely hypersensitive to DNA damage induced by the proton Bragg peak, which is characterized by higher density ionization.
Details
- Title: Subtitle
- Inhibition of ATM Induces Hypersensitivity to Proton Irradiation by Upregulating Toxic End Joining
- Creators
- Qin Zhou - Mayo ClinicMichelle E. Howard - Mayo ClinicXinyi Tu - Mayo ClinicQian Zhu - Mayo ClinicJanet M. Denbeigh - Mayo ClinicNicholas B. Remmes - Mayo ClinicMichael G. Herman - Mayo ClinicChris J. Beltran - Mayo ClinicJian Yuan - Mayo ClinicPatricia T. Greipp - Mayo ClinicJudy C. Boughey - Department of Surgery, Mayo ClinicLiewei Wang - Mayo ClinicNeil Johnson - Fox Chase Cancer CenterMatthew P. Goetz - Mayo ClinicJann N. Sarkaria - Mayo ClinicZhenkun Lou - Mayo ClinicRobert W. Mutter - Mayo Clinic
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.81(12), pp.3333-3346
- Publisher
- Amer Assoc Cancer Research
- DOI
- 10.1158/0008-5472.CAN-20-2960
- PMID
- 33597272
- PMCID
- PMC8260463
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Number of pages
- 14
- Grant note
- P50CA116201 / NCI of the NIH K12 HD065987 / Mayo Clinic Research Pipeline K2R Award American Society for Radiation Oncology
- Language
- English
- Date published
- 06/15/2021
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984312980802771
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