Stochastic fluctuations in apoptotic threshold of tumor cells can enhance apoptosis and combat fractional killing

Fractional killing, which is a significant impediment to successful
chemotherapy, is observed even in a population of genetically identical
cancer cells exposed to apoptosis-inducing agents. This phenomenon arises
not from genetic mutation but from cell-to-cell variation in the
activation timing and level of the proteins that regulate apoptosis. To
understand the mechanism behind the phenomenon, we formulate complex
fractional killing processes as a first-passage time (FPT) problem with a
stochastically fluctuating boundary. Analytical calculations are performed
for the FPT distribution in a toy model of stochastic p53 gene expression,
where the cancer cell is killed only when the p53 expression level crosses
an activity apoptotic threshold. Counterintuitively, we find that
threshold fluctuations can effectively enhance cellular killing by
significantly decreasing the mean time that the p53 protein reaches the
threshold level for the first time. Moreover, faster fluctuations lead to
the killing of more cells. These qualitative results imply that dynamic
variability in threshold is an unneglectable stochastic source, and can be
taken as a strategy for combating fractional killing of cancer cells.