Understanding the Mechanisms by Which Epigenetic Modifiers Avert Therapy Resistance in Cancer

Abstract

The development of resistance to anti-cancer therapeutics remains one of the core issues preventing the improvement of survival rates in cancer. Therapy resistance can arise in a multitude of ways, including the accumulation of epigenetic alterations in cancer cells. By remodeling DNA methylation patterns or modifying histone proteins during oncogenesis, cancer cells reorient their epigenomic landscapes in order to aggressively resist anti-cancer therapy. To combat these chemoresistant effects, epigenetic modifiers such as DNA hypomethylating agents, histone deacetylase inhibitors, histone demethylase inhibitors, along with others have been used. While these modifiers have achieved moderate success when used either alone or in combination with one another, the most positive outcomes were achieved when they were used in conjunction with conventional anti-cancer therapies. Epigenome modifying drugs have succeeded in sensitizing cancer cells to anti-cancer therapy via a variety of mechanisms: disrupting pro-survival/anti-apoptotic signaling, restoring cell cycle control and preventing DNA damage repair, suppressing immune system evasion, regulating altered metabolism, disengaging pro-survival microenvironmental interactions and increasing protein expression for targeted therapies. In this review, we explore different mechanisms by which epigenetic modifiers induce sensitivity to anti-cancer therapies and encourage the further identification of the specific genes involved with sensitization to facilitate development of clinical trials.

Keywords: cancer; chemoresistance; epigenetic aberrations; epigenetic combination therapies; epigenetic drugs; mechanism.

Figure 1

Hallmarks of Epigenetic Alteration-Induced Therapy Resistance Epigenetic dysregulation is a driving force in oncogenesis and the development of therapy resistance. (1) Increased pro-survival signaling (depicted by enhanced phosphorylation and activation of kinases such as Akt) can inhibit the expression of death proteins to promote cancer cell survival. The gene expression of death proteins (shown as transcriptional inhibition at the gene promoter) can also be disrupted, culminating in increased cell survival. (2) Aberrant cell cycling is caused by the over/under-expression of proliferative/checkpoint proteins (blue block with promoter), or increased activation of signaling pathways (shown by increased phosphorylation/activation) related to proliferation. DNA damage repair is augmented by an increased expression of repair proteins and disruption of checkpoint signaling. (3) Aberrant intracellular signaling can also alter cytokine expression and lead to reduced cytotoxic T lymphocyte (CTL) recruitment. Silencing of immune cell antigen targets can also suppress immune targeting of cancer cells (NK, natural killer). Increased expression of PD-L1 (green arrow and blue triangle) on cancer cells can augment the immune checkpoint response, resulting in T cell apoptosis. (4) Increased cellular adhesion within the bone marrow microenvironment (yellow block) in hematologic malignancies activates intracellular signaling pathways that protect malignant cells (blue spheres) from anti-cancer. Epithelial to mesenchymal transition (EMT) dislodges cancer cells (green blocks) from the solid tumor microenvironment and is the first step in metastasis. (5) Irregular cellular metabolism via overactive glucose metabolism leads to the Warburg effect favoring anabolic glycolysis over oxidative phosphorylation, and can render cells resistant to chemotherapeutics or antimetabolites. Resistance mechanisms are not restricted to just one of the categories; often with multiple categories being involved simultaneously.