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

Abstract

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.

Keywords:

• apoptotic threshold
• chemoresistance
• intratumor heterogeneity
• mitochondrial priming
• tubulin inhibitors

Financial & competing interests disclosure

The article was funded by NIH. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• Interphase processes are likely the chief targets of microtubule-targeting agents (MTAs) in many patients’ tumors.

• Thus, the notion that MTAs selectively target tumor cells because they are (seemingly) more highly proliferative than non-malignant cells is misguided.

• A more probable explanation for the degree of selectivity MTAs have for chemosensitive tumor cells is that these cells exist closer to the apoptotic threshold than non-malignant cells, an idea that is empirically supported even if it runs counter to the timeworn dictum that a defining feature of cancer is apoptosis reluctance.

• Many types of tumors exhibit profound genotypic and phenotypic cell-to-cell heterogeneity, with certain subpopulations of tumor cells more staunchly resisting the actions of MTAs.

• MTA-resistant clones may be less primed for apoptosis than MTA-sensitive ones.

• Cell-to-cell heterogeneity in Bcl-2 levels within tumors, which correlates with chemoresistance, supports the hypothesis that intratumor heterogeneity in proximity to the apoptotic threshold likely exists intratumorally and drives chemoresistance, although little research on the topic has been conducted.

• Chemotherapeutic regimens that incorporate drugs to selectively augment mitochondrial priming or to otherwise antagonize apoptosis reluctance (such as BH3 mimetics) in these clones may combat treatment failure and relapse.

• Given the reality of intratumor heterogeneity, it will be necessary to include heterogeneous culture systems and animal models in addition to the typically homogenous ones employed to generate translationally relevant conclusions that can improve chemotherapeutic regimens.

Notes