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Int J Radiat Oncol Biol Phys. 2019 Aug 16. pii: S0360-3016(19)33645-4. doi: 10.1016/j.ijrobp.2019.08.011. [Epub ahead of print]

Non-homologous end joining is more important than proton linear energy transfer in dictating cell death.

Author information

1
Departments ofRadiation Physics.
2
Departments ofRadiation Physics; Departments ofGraduate School of Biomedical Sciences.
3
Departments ofExperimental Radiation Oncology.
4
Departments ofExperimental Radiation Oncology; Departments ofRadiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
5
Departments ofTexas Children's Cancer Center and Department of Pediatrics, Baylor College of Medicine, Houston, TX.
6
Departments ofRadiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
7
Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX.
8
Departments ofRadiation Physics; Departments ofGraduate School of Biomedical Sciences,. Electronic address: gsawakuchi@mdanderson.org.

Abstract

PURPOSE:

To identify biological factors that may yield a therapeutic advantage of proton therapy versus photon therapy. Specifically, the role of non-homologous end-joining (NHEJ) and homologous recombination (HR) in the survival of cells in response to clinical photon and proton beams.

METHODS AND MATERIALS:

We irradiated HT1080, M059K (DNA-PKcs+/+), HCC1937 human cancer cell lines and their isogenic counterparts HT1080-shDNA-PKcs, HT1080-shRAD51IND, M059J (DNA-PKcs-/-) and HCC1937-BRCA1 (BRCA1 complemented) to assess cell clonogenic survival and γ-H2AX radiation-induced foci (RIF). Cells were irradiated with either clinically relevant photons or one of three proton linear energy transfer (LET) values.

RESULTS:

Our results indicate that NHEJ deficiency is more important in dictating cell survival than proton LET. Cells with disrupted HR through BRCA1 mutation showed increased radiosensitivity only for high-LET protons whereas RAD51 depletion showed increased radiosensitivity for both photons and protons. DNA double strand breaks (DSBs), assessed by γ-H2AX-RIF, showed greater numbers after 24 h in cells exposed to higher LET protons. We also observed that NHEJ-deficient cells were unable to repair the vast majority of DSBs after 24 h.

CONCLUSIONS:

BRCA1 mutation significantly sensitizes cells to protons but not photons. Loss of NHEJ renders cells hypersensitive to radiation, whereas the relative importance of HR increases with LET across several cell lines. This may be attributable to the more clustered damage induced by higher LET protons which are harder to repair through NHEJ. This highlights the importance of tumor biology in dictating treatment modality, as well as suggesting BRCA1 as a potential biomarker for proton therapy response. Our data also supports the use of pharmacologic inhibitors of DNA repair to enhance the sensitivity to different radiation types but also raises issues for normal tissue toxicity.

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