Chronorepair: Agent-Based Modelling of Charged Particle Survival Curves from Double-Strand Break Repair Kinetics
Abstract
Purpose
Mechanistic models can help us understand why hadrons kill cells more effectively than photons. We used ChronoRepair, an agent-based model that tracks individual double-strand breaks (DSB) through detection, repair, and cell-fate decisions, to identify which parameters drive the enhanced biological effect of protons and alpha particles.
Methods
ChronoRepair simulates radiation response using five mechanistically interpretable parameters. Two govern repair kinetics: detectRate (DSB recognition) and finishRate (repair completion); while thresholdForDeath, thresholdForCycleChange, and weightLethalityMisrepair govern cell fate. We fitted detectRate and finishRate to published x-ray gamma-H2AX foci kinetics in A549 cells, then held these fixed for protons and alphas. The sensitivity to this assumption was analyzed. Cell-fate parameters were independently fitted to the same cell line-published data for clonogenic survival for x-rays, 1-MeV protons (LET~25 keV/um), and 4-MeV alphas (LET~102 keV/um). Parameter uncertainty was estimated from 10 independent differential evolution fits. Initial DSB yields in nuclei were generated with TOPAS-nBio.
Results
Fitting foci data yielded detectRate=0.16 ± 0.03 s-1 and finishRate=0.0022 ± 0.0001 s-1. Sensitivity analysis showed low root mean square error (RMSE) for detectRate perturbations for protons and alphas, but higher RMSE for finishRate, indicating greater sensitivity to repair completion kinetics than detection. Particle survival parameters exhibited less sensitivity than photons, consistent with a simpler linear response. thresholdForDeath was the most constrained cell-fate parameter and was lowest for alphas, implying fewer DSBs are required to trigger death, consistent with more complex damage. weightLethalityMisrepair was also highest for alphas, indicating a greater impact of misrepairs. This may arise from the specific misrepairs induced by high-LET radiation, such as incorrect recombination between clustered DSBs. Proton parameters lay between photons and alphas, suggesting an LET-dependent trend.
Conclusion
ChronoRepair reproduces A549 survival across radiation qualities using mechanistically interpretable parameters. The enhanced biological effect of hadrons arises primarily from cell-fate thresholds, not altered repair kinetics.