Epigenetic therapy approaches in non-small cell lung cancer: Update and perspectives

Abstract

Non-small cell lung cancer (NSCLC) still constitutes the most common cancer-related cause of death worldwide. All efforts to introduce suitable treatment options using chemotherapeutics or targeted therapies have, up to this point, failed to exhibit a substantial effect on the 5-year-survival rate. The involvement of epigenetic alterations in the evolution of different cancers has led to the development of epigenetics-based therapies, mainly targeting DNA methyltransferases (DNMTs) and histone-modifying enzymes. So far, their greatest success stories have been registered in hematologic neoplasias. As the effects of epigenetic single agent treatment of solid tumors have been limited, the investigative focus now lies on combination therapies of epigenetically active agents with conventional chemotherapy, immunotherapy, or kinase inhibitors. This review includes a short overview of the most important preclinical approaches as well as an extensive discussion of clinical trials using epigenetic combination therapies in NSCLC, including ongoing trials. Thus, we are providing an overview of what lies ahead in the field of epigenetic combinatory therapies of NSCLC in the coming years.

Epithelial‐to‐mesenchymal transition in the context of epidermal growth factor receptor inhibition in non‐small‐cell lung cancer

“…LSD1 is frequently overexpressed in NSCLC, where it favours proliferation and invasiveness. The availability of LSD1 inhibitors could potentially facilitate the control of this function (Lv et al , ; Schiffmann et al , ).…”

Current Landscape of Epigenetics in Lung Cancer: Focus on the Mechanism and Application

“…A variety of known HDACi, including trichostatin A, SAHA, depsipeptide, and valproic acid, and some new HDACi, such as KD5170 and R306465, have been tested in lung cancer cell lines and transplantation models. In view of the limited effect of epigenetic monotherapy on solid tumors to improve the therapeutic effect, the combination of DNMTi or HDACi with conventional chemotherapy, kinase inhibitors, or immunotherapy has been intensively explored in prospective clinical trials [90][91][92]. ncRNAs are also important drug targets, and their mechanism of action is to enhance tumor suppressor genes or inhibit oncogenes.…”

Epigenetic Modifications and Potential Treatment Approaches in Lung Cancers

“…DNA DNMTs are molecules that transfer methyl groups to cytosines via S-adenosyl methionine (SAM). Hypo-and hyper-methylation of DNA may occur in any cancer cell and silence tumour suppressor genes or inactivate T-cell recognition genes, which provide immune response, or affect the genes that trigger metastasis, angiogenesis and invasion [74]. The most important investigational DNA methyltransferase inhibitors and their analogues are presented in Table 1 [74].…”