Polytherapy and Targeted Cancer Drug Resistance

Abstract

A current challenge in cancer treatment is drug resistance. Even the most effective therapies often fail to produce a complete and durable tumor response and ultimately give rise to therapy resistance and tumor relapse. However, how resistance arises in cancer remains incompletely understood. While drug resistance in cancer is thought to be driven by irreversible genetic mutations, emerging evidence also implicates reversible proteomic and epigenetic mechanisms in the development of drug resistance. Tumor microenvironment-mediated mechanisms and tumor heterogeneity can significantly contribute to cancer treatment resistance. Here, we discuss the diverse and dynamic strategies that cancers use to evade drug response, the promise of upfront combination and intermittent therapies and therapy switching in forestalling resistance, and epigenetic reprogramming to combat resistance.

Keywords: cancer evolution; drug resistance; epigenetics; genetics; molecular targets; polytherapy; targeted therapy.

Figure 1.. Different mechanisms of drug resistance in cancer.

Drug resistance is multifactorial and heterogenous and poses serious challenges to cancer treatment. The underlying mechanisms of drug resistance are diverse and complex, and often not mutually exclusive. Drug resistance is driven by both genetic and epigenetic mechanisms as well as by several other factors, including drug transporters and adaptive signaling events in tumor cells as well as tumor microenvironment features.

Figure 2.. Changes in tumor heterogeneity during tumor progression and treatment.

Tumor heterogeneity arises due to mutations acquired by daughter cells upon clonal outgrowth of a single founder cell (red) and increases sharply with further development into subclones (different colors reflect different subclones/subpopulations). Some new mutations lead to accelerated growth (for example green and orange subclones). Drug treatment leads to selective survival of a drug resistant clone (orange subclone) and elimination of drug-sensitive subclones (for example green and red subclones) that reduces genetic heterogeneity transiently. Heterogeneity is re-established rapidly through acquisition of mutations by daughter cells of the resistant clone.

Figure 3.. Aggressive therapy versus chronic control of tumors.

There is a fine balance between sustained maximum-dose density therapy and intermittent minimum necessary-dose therapy. Continuous maximum-dose density therapy is based on the principle of eradicating the tumor as swiftly as possible so that drug-resistance does not emerge. However, such rapid and aggressive treatment regimens eliminate the bulk of the tumor cells which are drug sensitive but also select for the minor, drug resistant sub-population already present within the tumor which ultimately takes over the entire tumor and promotes therapy failure. By contrast, in intermittent minimum necessary-dose therapy the idea is to contain the tumors at a fixed tolerable level to allow for expansion of drug sensitive cells at the expense of resistant ones. Although the tumor will increase in size between treatments, it will continue to remain sensitive to therapy overall. Adapted from [8, 102].