Epigenetic regulation of radioresistance: insights from preclinical and clinical studies

ABSTRACT

Introduction

Oftentimes, radiation therapy (RT) is ineffective due to the development of radioresistance (RR). However, studies have shown that targeting epigenetic modifiers to enhance radiosensitivity represents a promising direction of clinical investigation.

Areas covered

This review discusses the mechanisms by which epigenetic modifiers alter radiosensitivity through dysregulation of MAPK-ERK and AKT-mTOR signaling. Finally, we discuss the clinical directions for targeting epigenetic modifiers and current radiology techniques used in the clinic.

Methodology

We searched PubMed and ScienceDirect databases from April 4^th, 2022 to October 18^th, 2022. We examined 226 papers related to radioresistance, epigenetics, MAPK, and PI3K/AKT/mTOR signaling. 194 papers were selected for this review. Keywords used for this search include, ‘radioresistance,’ ‘radiosensitivity,’ ‘radiation,’ ‘radiotherapy,’ ‘particle radiation,’ ‘photon radiation,’ ‘epigenetic modifiers,’ ‘MAPK,’ ‘AKT,’ ‘mTOR,’ ‘cancer,’ and ‘PI3K.’ We examined 41 papers related to clinical trials on the aforementioned topics. Outcomes of interest were safety, overall survival (OS), dose-limiting toxicities (DLT), progression-free survival (PFS), and maximum tolerated dose (MTD).

Expert opinion

Current studies focusing on epigenetic mechanisms of RR strongly support the use of targeting epigenetic modifiers as adjuvants to standard cancer therapies. To further the success of such treatments and their clinical benefit , both preclinical and clinical studies are needed to broaden the scope of known radioresistant mechanisms.

KEYWORDS:

• Cancer
• DDR
• DNA damage
• epigenetics
• MAPK-ERK signaling
• PI3K-AKT-mTOR-signaling
• radiation
• radioresistance
• radiosensitivity

Article highlights

• Cancer cells are able to evade the deleterious effects of ionizing radiation (IR) through the development of radioresistance (RR), which includes alterations in cell cycle regulation and DNA damage repair (DDR)

• Epigenetic modifiers play a crucial role in the development of RR, particularly by regulating gene expression through methylation, phosphorylation, and acetylation of DNA, histones, and RNAs.

• Many studies have demonstrated that dysregulation of MAPK-ERK and PI3K-AKT-mTOR signaling induced by epigenetic reprogramming represents a prominent mechanism by which RR develops.

• Pre-clinical studies have demonstrated the need for investigating the clinical/therapeutic efficacy of targeting epigenetic modifiers. Clinical trials using such novel inhibitors are now being investigated and have shown promising results.

This box summarizes key points contained in the article.

Acknowledgments

Alexis Reinders would like to thank the support from the Summer 2022 Craig fellowship program at the University of Illinois College of Medicine. The authors would like to thank Christina Constantinidou for helping with the manuscript formatting.

Declaration of interests

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. All figures and tables presented in this work have been originally created for the purpose of this manuscript and have not been published elsewhere. Molecule Sketch software was used to create Figure 3 and Figure 4.

Reviewer disclosures

Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.