Chapter Eight - The epigenetic regulation of cancer cell recovery from therapy exposure and its implications as a novel therapeutic strategy for preventing disease recurrence

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Abstract

The ultimate goal of cancer therapy is the elimination of disease from patients. Most directly, this occurs through therapy-induced cell death. Therapy-induced growth arrest can also be a desirable outcome, if prolonged. Unfortunately, therapy-induced growth arrest is rarely durable and the recovering cell population can contribute to cancer recurrence. Consequently, therapeutic strategies that eliminate residual cancer cells reduce opportunities for recurrence. Recovery can occur through diverse mechanisms including quiescence or diapause, exit from senescence, suppression of apoptosis, cytoprotective autophagy, and reductive divisions resulting from polyploidy. Epigenetic regulation of the genome represents a fundamental regulatory mechanism integral to cancer-specific biology, including the recovery from therapy. Epigenetic pathways are particularly attractive therapeutic targets because they are reversible, without changes in DNA, and are catalyzed by druggable enzymes. Previous use of epigenetic-targeting therapies in combination with cancer therapeutics has not been widely successful because of either unacceptable toxicity or limited efficacy. The use of epigenetic-targeting therapies after a significant interval following initial cancer therapy could potentially reduce the toxicity of combination strategies, and possibly exploit essential epigenetic states following therapy exposure. This review examines the feasibility of targeting epigenetic mechanisms using a sequential approach to eliminate residual therapy-arrested populations, that might possibly prevent recovery and disease recurrence.

Introduction

Cancer treatments, which include chemotherapy, radiotherapy, surgery, and more recently immunotherapy and targeted therapy, have unquestionably improved the quality of life and patient survival (Siegel, Miller, & Jemal, 2020). Within the last several decades, the 5-year survival rate for most cancers has increased, in some cases dramatically (i.e., lung and melanoma) (Siegel et al., 2020). Despite these advances, cancer still remains the second leading cause of death in the United States. Mortality from cancer is due to progressive disease, or in cases of initial complete response, recurrence (National Center for Health Statistics (US), 2017). Consequently, developing novel therapies to improve response in tumors that do not completely respond to traditional therapy and to prevent tumors that initially experience a complete response from reoccurring is currently a major focus of the cancer research community.

The primary goal of cancer therapies (chemotherapy or radiation) is cancer cell death, because cancer cells that die cannot recover and contribute to disease recurrence. Moreover, depending on the mechanism of therapy-induced death, this event can contribute significantly to stimulating antitumor immune responses (Galluzzi, Buque, Kepp, Zitvogel, & Kroemer, 2017). Mechanisms of cell death commonly include apoptosis, resulting from excessive damage to cellular components (DNA, mitochondria, plasma membrane, etc.), ferroptosis, a distinct iron-dependent cell death pathway, mitotic catastrophe, which can result from the inhibition of chromosome segregation from microtubule inhibitors, and a cytotoxic form of autophagy that can occur from a combination of endoplasmic reticulum (ER) stress and DNA damage resulting in the immunogenic death of the cell (Fig. 1A) (Galluzzi et al., 2018).

From a practical standpoint, therapies do not result in the death of all tumor cells, as a population of cells are refractory to, or initially respond to but then recover from, exposure to treatment. Recovering populations were reported in some of the earliest studies examining the effects of chemotherapy on cancer cells (Barranco & Flournoy, 1977; Braun & Hahn, 1975). Such incomplete responses, leading to disease recurrence, are due to an inability to achieve lethal doses of therapy in the tumor, as well as a tumor cells intrinsic resistance to therapy. Because of its important role in cancer mortality, the control and prevention of recurrence is critical for improving survival rates. How both local and distant recurrence occur has been investigated intensively for decades (Mahvi, Liu, Grinstaff, Colson, & Raut, 2018; Riggio, Varley, & Welm, 2021). By definition, recurrence occurs when cancer cells exhibit a drug-tolerant persister (DTP) phenotype, which broadly describes a phenotype in which a subpopulation of cells is more resistant to the therapy (Dhanyamraju, Schell, Amin, & Robertson, 2022) (Fig. 1B). Several mechanisms, including the existence of a small preexisting therapy-resistant population, the selection of rare genetic mutations and/or heritable epigenetic changes that confer acquired resistance to therapy, and the escape of cancer cells from sublethal therapy exposure are likely to operate in concert to contribute to disease reoccurrence. Various modifications to therapeutic strategies have been developed to target such subpopulations, most notably the use of combination strategies to forestall or prevent the selection of rare clones resistant to single agents (Fisusi & Akala, 2019; Patel & Minn, 2018). However, in most cases, these approaches are not curative, and as a consequence, continuing to develop novel ways to target these populations will be essential to preventing disease recurrence.

One plausible strategy for eliminating cancer cells recovering from therapy involves targeting epigenetic pathways. This approach has been aggressively investigated over the last few decades, with the primary objective of sensitizing DTP cancer cells prior to or coincident with therapy (Liau et al., 2017; Vinogradova et al., 2016). Such sensitization strategies have as their goal disabling of epigenetic pathways that may be essential for DTP cell survival, and, as a result, the prevention of recurrence due to residual tumor cell elimination. While this strategy has been extensively pursued, it has yielded very limited success in solid tumors in the clinic due to toxicity from combining epigenetic with standard of care therapies, as well as minimal antitumor responses (Morel, Jeffery, Aspeslagh, Almouzni, & Postel-Vinay, 2020).

An alternative and infrequently pursued approach involves a strategy designed to convert cancer cells that have partially responded to initial primary therapy to complete responders using a secondary epigenetic-targeted therapy. This approach is based on the hypothesis that persister cells may be particularly susceptible to either cell death or growth arrest in response to epigenetic agents. This strategy could be particularly beneficial as, for example, cells recovering from therapy-induced senescence exhibit stem cell-like properties and have been shown to be particularly aggressive and tumorigenic (Milanovic et al., 2018). Specifically targeting therapy-arrested senescent cells is currently being actively pursued through the use of senolytics, a class of agents that exhibit selective toxicity to senescent cells (Wang, Lankhorst, & Bernards, 2022; Zhu et al., 2015). However, this phenomenon can also occur by targeting epigenetic pathways essential for maintaining a variety of prosurvival cell stress responses in the residual therapy-exposed cancer cell population. Because epigenetic events play key regulatory roles in diverse cellular stress response pathways (see discussion below), it is plausible that these pathways could be targeted to disable survival-related responses in therapy-exposed cancer cells. Such actions may drive the residual surviving population into one or more forms of cell death. This review summarizes the known epigenetic mechanisms that regulate therapy-induced survival pathways, and provides a rational road map for employing epigenetic-targeting small molecules as a viable strategy for eradicating the residual population of surviving persister cells.

Section snippets

A short primer on epigenetics

The field of epigenetics has a complex history (Peixoto, Cartron, Serandour, & Hervouet, 2020) and has been the subject of extensive research efforts over the last several decades (The ENCODE Project Consortium et al., 2020). Epigenetics represents the study of heritable phenotypic changes that do not involve alterations in the DNA sequence (Berger, Kouzarides, Shiekhattar, & Shilatifard, 2009). Epigenetic marks serve as regulatory pathways that act in addition to existing genetic regulatory

The limited success of epigenetic-targeted therapies treating solid tumors

Epigenetics plays a fundamental role in cancer biology, a view that is supported by the elevation of “epigenetic programming” as one of the hallmarks of cancer as recently proposed by Hanahan (Hanahan, 2022). It has been known for decades that epigenetics plays an important role in the ability of hematologic malignancies to respond to, and recover from, exposure to cytotoxic chemotherapy (Kuendgen & Gattermann, 2007; Kuendgen et al., 2004; Schwartsmann et al., 1997). In addition, epigenetic

A proposed novel use for epigenetic-targeted therapies

As noted previously, the two major barriers to the success of epigenetic strategies in solid tumors are unacceptable toxicity and limited effectiveness (Morel et al., 2020). The latter has been postulated to stem from poor penetration of epigenetic therapies into solid tumors and the redundancy of epigenetic pathways in cancer cells regulating cancer biology (Gottesman, Lavi, Hall, & Gillet, 2016). The former problem is not unique to epigenetic therapies, and is observed in the case of diverse

Pretherapy quiescent state

Quiescence is a mechanism of dormancy by which tumors cells persist in a patient for extended periods of time and provides a mechanism by which tumor cells can evade the effects of cytotoxic chemotherapy. Quiescence is also a normal and reversible process of embryonic development and adult tissue homeostasis that is required for both stem and nonstem cells alike to survive stressful microenvironments (Marescal & Cheeseman, 2020). In the context of cancer, quiescence is observed in many tumor

Strategies to prevent recovery from therapy exposure

There are several broad strategies for utilizing epigenetic-targeted therapies to eliminate therapy-arrested cells at a significant interval after therapy exposure (Fig. 4). Two leading strategies can be proposed. The first can be thought of as a “lock-in” strategy which attempts to maintain a stable form of therapy-induced proliferative arrest, and the second a “lock-out” strategy which attempts to induce therapy-arrested cells to undergo cell death. Similar strategies have been proposed for

Future directions

In this review, we propose a new strategy for the use of epigenetic-targeting therapies in the prevention of recurrent disease under conditions of partial or complete response. We hypothesize that the use epigenetic-targeting therapies in sequence, a significant interval after the primary cytotoxic therapy, could reduce the toxicity from cotreatments and could target novel epigenetic states that have been established posttherapy exposure.

In the past, epigenetic-targeting therapies have been

Acknowledgments

The authors would like to acknowledge our funding sources that contributed to this work. These include a grant from the DoD BCRP W81XWH1910489 to J.L., a Closing the Gap pilot grant from the Virginia Commonwealth University (VCU) Massey Cancer Center to J.L. and H.B. In addition, we received internal funds and support from the VCU School of Medicine, the VCU Wright Center for Clinical and Translational Research. Biorender was used to create figures. We would like to acknowledge Heidi Sankala

References (245)

  • G.P. Dimri

    What has senescence got to do with cancer?

    Cancer Cell

    (2005)
  • D. Hanahan et al.

    Hallmarks of cancer: The next generation

    Cell

    (2011)
  • K. Hinohara et al.

    KDM5 histone demethylase activity links cellular transcriptomic heterogeneity to therapeutic resistance

    Cancer Cell

    (2019)
  • T. Ito et al.

    Regulation of cellular senescence by polycomb chromatin modifiers through distinct DNA damage- and histone methylation-dependent pathways

    Cell Reports

    (2018)
  • C.H. Jung et al.

    mTOR regulation of autophagy

    FEBS Letters

    (2010)
  • A. Kuendgen et al.

    Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid

    Blood

    (2004)
  • R. Labianca et al.

    Intermittent versus continuous chemotherapy in advanced colorectal cancer: A randomised 'GISCAD' trial

    Annals of Oncology

    (2011)
  • J.M. Adams et al.

    The Bcl-2 apoptotic switch in cancer development and therapy

    Oncogene

    (2007)
  • K. Agger et al.

    The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence

    Genes & Development

    (2009)
  • U. Akar et al.

    Silencing of Bcl-2 expression by small interfering RNA induces autophagic cell death in MCF-7 breast cancer cells

    Autophagy

    (2008)
  • Y. Akkoc et al.

    Autophagy and cancer dormancy

    Frontiers in Oncology

    (2021)
  • D.A. Alcorta et al.

    Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts

    Proceedings of the National Academy of Sciences of the United States of America

    (1996)
  • F. Angeletti et al.

    Inhibition of the autophagy pathway synergistically potentiates the cytotoxic activity of givinostat (ITF2357) on human glioblastoma cancer stem cells

    Frontiers in Molecular Neuroscience

    (2016)
  • H.F. Aqbi et al.

    Autophagy-deficient breast cancer shows early tumor recurrence and escape from dormancy

    Oncotarget

    (2018)
  • A.Z. Ayob et al.

    Cancer stem cells as key drivers of tumour progression

    Journal of Biomedical Science

    (2018)
  • M. Barradas et al.

    Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS

    Genes & Development

    (2009)
  • S.C. Barranco et al.

    Cell killing, kinetics, and recovery responses induced by 1,2:5,6-dianhydrogalactitol in dividing and nondividing cells in vitro

    Journal of the National Cancer Institute

    (1977)
  • S.E. Bates

    Epigenetic therapies for cancer

    The New England Journal of Medicine

    (2020)
  • B. Beck et al.

    Unravelling cancer stem cell potential

    Nature Reviews. Cancer

    (2013)
  • R.R. Begicevic et al.

    ABC transporters in cancer stem cells: Beyond chemoresistance

    International Journal of Molecular Sciences

    (2017)
  • S.L. Berger et al.

    An operational definition of epigenetics

    Genes & Development

    (2009)
  • K. Bonitto et al.

    Is there a histone code for cellular quiescence?

    Frontiers in Cell and Development Biology

    (2021)
  • N. Bora-Singhal et al.

    Novel HDAC11 inhibitors suppress lung adenocarcinoma stem cell self-renewal and overcome drug resistance by suppressing Sox2

    Scientific Reports

    (2020)
  • A.P. Bracken et al.

    The polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells

    Genes & Development

    (2007)
  • J. Braun et al.

    Enhanced cell killing by bleomycin and 43 degrees hyperthermia and the inhibition of recovery from potentially lethal damage

    Cancer Research

    (1975)
  • H. Bulstrode et al.

    Elevated FOXG1 and SOX2 in glioblastoma enforces neural stem cell identity through transcriptional control of cell cycle and epigenetic regulators

    Genes & Development

    (2017)
  • V. Buocikova et al.

    Epigenetics in breast cancer therapy—New strategies and future nanomedicine perspectives

    Cancers

    (2020)
  • A.M. Calcagno et al.

    Prolonged drug selection of breast cancer cells and enrichment of cancer stem cell characteristics

    Journal of the National Cancer Institute

    (2010)
  • B.C. Capell et al.

    MLL1 is essential for the senescence-associated secretory phenotype

    Genes & Development

    (2016)
  • C. Caslini et al.

    HDAC7 regulates histone 3 lysine 27 acetylation and transcriptional activity at super-enhancer-associated genes in breast cancer stem cells

    Oncogene

    (2019)
  • J.C. Chang

    Cancer stem cells: Role in tumor growth, recurrence, metastasis, and treatment resistance

    Medicine (Baltimore)

    (2016)
  • B.D. Chang et al.

    A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents

    Cancer Research

    (1999)
  • B.D. Chang et al.

    Role of p53 and p21waf1/cip1 in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugs

    Oncogene

    (1999)
  • S. Chen et al.

    The residual tumor autophagy marker LC3B serves as a prognostic marker in local advanced breast cancer after neoadjuvant chemotherapy

    Clinical Cancer Research

    (2013)
  • W. Chen et al.

    Cancer stem cell quiescence and plasticity as major challenges in cancer therapy

    Stem Cells International

    (2016)
  • K. Chen et al.

    Understanding and targeting cancer stem cells: Therapeutic implications and challenges

    Acta Pharmacologica Sinica

    (2013)
  • T.H. Cheung et al.

    Molecular regulation of stem cell quiescence

    Nature Reviews. Molecular Cell Biology

    (2013)
  • G. Cimino et al.

    Sequential valproic acid/all-trans retinoic acid treatment reprograms differentiation in refractory and high-risk acute myeloid leukemia

    Cancer Research

    (2006)
  • C.R. Clapier et al.

    The biology of chromatin remodeling complexes

    Annual Review of Biochemistry

    (2009)
  • J.P. Coppe et al.

    The senescence-associated secretory phenotype: The dark side of tumor suppression

    Annual Review of Pathology

    (2010)
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