Die-hard survivors: heterogeneity in apoptotic thresholds may underlie chemoresistance

The unmatched efficacy of microtubule-targeting agents (MTAs) as chemotherapeutics was once assumed to originate from their impact on mitotic processes; however, this misconception is being eroded by amassing data that MTAs instead target interphase functions in patients' tumors. What remains murky is how MTAs target malignant cells over non-malignant ones if proliferation rates do not distinguish them. In many instances, malignant cells are actually more 'primed' for apoptosis than non-malignant ones. Nevertheless, even if most cells within the tumor are more apoptosis-susceptible than those in healthy tissues, there likely exist small subpopulations of apoptosis-resistant clones that engender incomplete responses to MTAs and relapse. Therefore, intratumor heterogeneity in terms of proximity to the apoptotic threshold must be better understood to facilitate the design of chemotherapeutic regimens, which may benefit from including drugs like BH3 mimetics that help in lowering the apoptotic threshold of tumor cells within these chemoresistant subpopulations.