Anestopoulos I, Kyriakou S, Tragkola V, Paraskevaidis I, Tzika E, Mitsiogianni M, Deligiorgi M V, Petrakis G, Trafalis D T, Botaitis S, Giatromanolaki A, Koukourakis M I, Franco R, Pappa A, Panayiotidis M I
Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
Medpace UK Ltd, London, UK.
Pharmacol Ther. 2022 Dec;240:108301. doi: 10.1016/j.pharmthera.2022.108301. Epub 2022 Oct 23.
Malignant melanoma is the most lethal type of skin cancer with high rates of mortality. Although current treatment options provide a short-clinical benefit, acquired-drug resistance highlights the low 5-year survival rate among patients with advanced stage of the disease. In parallel, the involvement of an aberrant epigenetic landscape, (e.g., alterations in DNA methylation patterns, histone modifications marks and expression of non-coding RNAs), in addition to the genetic background, has been also associated with the onset and progression of melanoma. In this review article, we report on current therapeutic options in melanoma treatment with a focus on distinct epigenetic alterations and how their reversal, by specific drug compounds, can restore a normal phenotype. In particular, we concentrate on how single and/or combinatorial therapeutic approaches have utilized epigenetic drug compounds in being effective against malignant melanoma. Finally, the role of deregulated epigenetic mechanisms in promoting drug resistance to targeted therapies and immune checkpoint inhibitors is presented leading to the development of newly synthesized and/or improved drug compounds capable of targeting the epigenome of malignant melanoma.
恶性黑色素瘤是最致命的皮肤癌类型，死亡率很高。尽管目前的治疗方法能带来短期临床益处，但获得性耐药凸显了晚期疾病患者5年生存率较低的问题。同时，除了遗传背景外，异常的表观遗传格局（例如DNA甲基化模式改变、组蛋白修饰标记和非编码RNA的表达）也与黑色素瘤的发生和进展有关。在这篇综述文章中，我们报告了黑色素瘤治疗的当前治疗选择，重点关注不同的表观遗传改变，以及特定药物化合物如何逆转这些改变以恢复正常表型。特别是，我们专注于单一和/或联合治疗方法如何利用表观遗传药物化合物有效对抗恶性黑色素瘤。最后，阐述了失调的表观遗传机制在促进对靶向治疗和免疫检查点抑制剂的耐药性中的作用，从而促使开发能够靶向恶性黑色素瘤表观基因组的新合成和/或改良药物化合物。
