LAUSR

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 4th, 2022 to October 18th, 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.