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Role of Double Strand Break DNA Repair Deficiency On the Sensitivity of Cells to Therapeutic Proton Beams

S Bright1 , D Flint1 , C McFadden1 , D Yoon1 , A Aroumougame2 ,G Sawakuchi1* , (1) MD Anderson cancer center, Houston, Texas, (2) UT Southwestern, Dallas, Texas


(Tuesday, 7/31/2018) 1:45 PM - 3:45 PM

Room: Karl Dean Ballroom A1

Purpose: As the LET of proton beams increases the quality of biological damage changes. At the DNA level, this requires a more sophisticated repair process called homologous recombination (HR) as opposed to non-homologous end joining (NHEJ), which generally repairs more simple lesions. The goal of this work is to assess the importance of double strand break repair pathways on determining the LET dependence of RBE.

Methods: Various cell lines harboring different genetic abnormalities were exposed to an un-modulated 100 MeV proton beam in three different depths to provide three different dose averaged LET values (1.3, 2.8 and 11.1 keV/μm). Clonogenic survival was assessed and RBE was calculated for 10% survival in reference to a clinical 6 MV x-ray beam. DNA damage was quantified in each cell line using the double strand break markers gamma-H2AX and 53BP1.

Results: We have identified that RBE is dependent on LET but is heavily influenced by genetic abnormalities in DNA repair. We also found that radioresistance to x-rays correlate with higher RBE. Cells that were unable to perform NHEJ, but could perform HR, and theoretically repair more complex lesions showed little LET dependence (RBE of 0.95 ± 0.26 with 11.1 keV/µm protons). In contrast, cells unable to perform HR had an RBE that was influenced by LET (RBE of 1.46 ± 0.16 and 1.35 ± 0.04 for HR deficient/proficient cells, respectively).

Conclusion: Our data suggest that increasing proton RBE is partly driven by biological aspects such as repair abnormalities. HR defects are much more important than NHEJ for establishing RBE dependence on LET. Therefore it may be possible to identify individuals who will respond favorably to proton therapy based on genetic background, particularly relating to DNA repair. We are currently investigating DNA damage complexity to determine if this is the link between LET and RBE.


Protons, RBE, LET


TH- Radiobiology(RBio)/Biology(Bio): RBio- Particle therapy- Protons

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