  We employ a multi-scale mechanistic approach to investigate radiation induced
cell toxicities and deactivation mechanisms as a function of linear energy
transfer in hadron therapy. Our theoretical model consists of a system of
Markov chains in microscopic and macroscopic spatio-temporal landscapes, i.e.,
stochastic birth-death processes of cells in millimeter-scale colonies that
incorporates a coarse-grained driving force to account for microscopic
radiation induced damage. The coupling, hence the driving force in this
process, stems from a nano-meter scale radiation induced DNA damage that
incorporates the enzymatic end-joining repair and mis-repair mechanisms. We use
this model for global fitting of the high-throughput and high accuracy
clonogenic cell-survival data acquired under exposure of the therapeutic
scanned proton beams, the experimental design that considers $\gamma$-H2AX as
the biological endpoint and exhibits maximum observed achievable dose and LET,
beyond which the majority of the cells undergo collective biological
deactivation processes. An estimate to optimal dose and LET calculated from
tumor control probability by extension to $~ 10^6$ cells per $mm$-size voxels
is presented. We attribute the increase in degree of complexity in chromosome
aberration to variabilities in the observed biological responses as the beam
linear energy transfer (LET) increases, and verify consistency of the predicted
cell death probability with the in-vitro cell survival assay of approximately
100 non-small cell lung cancer (NSCLC) cells.
