Rubanov Andrey, Berico Pietro, Hernando Eva
Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA.
Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, NYU Langone Health, New York, NY 10016, USA.
Cancers (Basel). 2022 Nov 28;14(23):5858. doi: 10.3390/cancers14235858.
Melanoma is an aggressive skin cancer reliant on early detection for high likelihood of successful treatment. Solar UV exposure transforms melanocytes into highly mutated tumor cells that metastasize to the liver, lungs, and brain. Even upon resection of the primary tumor, almost thirty percent of patients succumb to melanoma within twenty years. Identification of key melanoma genetic drivers led to the development of pharmacological BRAF and MEK inhibitors, significantly improving metastatic patient outcomes over traditional cytotoxic chemotherapy or pioneering IFN-α and IL-2 immune therapies. Checkpoint blockade inhibitors releasing the immunosuppressive effects of CTLA-4 or PD-1 proved to be even more effective and are the standard first-line treatment. Despite these major improvements, durable responses to immunotherapy and targeted therapy have been hindered by intrinsic or acquired resistance. In addition to gained or selected genetic alterations, cellular plasticity conferred by epigenetic reprogramming is emerging as a driver of therapy resistance. Epigenetic regulation of chromatin accessibility drives gene expression and establishes distinct transcriptional cell states. Here we review how aberrant chromatin, transcriptional, and epigenetic regulation contribute to therapy resistance and discuss how targeting these programs sensitizes melanoma cells to immune and targeted therapies.
黑色素瘤是一种侵袭性皮肤癌，其成功治疗的可能性很大程度上依赖于早期检测。日光紫外线暴露会将黑素细胞转化为高度突变的肿瘤细胞，这些细胞会转移至肝脏、肺部和大脑。即使切除原发性肿瘤，仍有近30%的患者会在20年内死于黑色素瘤。对黑色素瘤关键基因驱动因素的识别促使了BRAF和MEK药理抑制剂的研发，相较于传统的细胞毒性化疗或开创性的IFN-α和IL-2免疫疗法，显著改善了转移性患者的治疗效果。释放CTLA-4或PD-1免疫抑制作用的检查点阻断抑制剂被证明更为有效，是标准的一线治疗方法。尽管有这些重大进展，但免疫疗法和靶向疗法的持久反应一直受到内在或获得性耐药性的阻碍。除了获得性或选择性基因改变外，表观遗传重编程赋予的细胞可塑性正在成为治疗耐药性的驱动因素。染色质可及性的表观遗传调控驱动基因表达并建立不同的转录细胞状态。在这里，我们综述异常染色质、转录和表观遗传调控如何导致治疗耐药性，并讨论针对这些程序如何使黑色素瘤细胞对免疫疗法和靶向疗法敏感。
