Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
Int J Mol Sci. 2021 May 12;22(10):5115. doi: 10.3390/ijms22105115.
Melanoma is one of the most aggressive forms of skin cancer and is therapeutically challenging, considering its high mutation rate. Following the development of therapies to target BRAF, the most frequently found mutation in melanoma, promising therapeutic responses were observed. While mono- and combination therapies to target the MAPK cascade did induce a therapeutic response in BRAF-mutated melanomas, the development of resistance to MAPK-targeted therapies remains a challenge for a high proportion of patients. Resistance mechanisms are varied and can be categorised as intrinsic, acquired, and adaptive. RASSF1A is a tumour suppressor that plays an integral role in the maintenance of cellular homeostasis as a central signalling hub. RASSF1A tumour suppressor activity is commonly lost in melanoma, mainly by aberrant promoter hypermethylation. RASSF1A loss could be associated with several mechanisms of resistance to MAPK inhibition considering that most of the signalling pathways that RASSF1A controls are found to be altered targeted therapy resistant melanomas. Herein, we discuss resistance mechanisms in detail and the potential role for RASSF1A reactivation to re-sensitise BRAF mutant melanomas to therapy.
黑色素瘤是最具侵袭性的皮肤癌之一，由于其高突变率，治疗具有挑战性。在开发针对黑色素瘤中最常见突变的 BRAF 靶点的疗法之后，观察到了有希望的治疗反应。虽然针对 MAPK 级联的单药和联合治疗确实诱导了 BRAF 突变黑色素瘤的治疗反应，但 MAPK 靶向治疗的耐药性仍然是很大一部分患者面临的挑战。耐药机制多种多样，可以分为内在的、获得性的和适应性的。RASSF1A 是一种肿瘤抑制因子，作为中央信号枢纽，在维持细胞内稳态方面发挥着重要作用。RASSF1A 肿瘤抑制活性在黑色素瘤中通常丧失，主要是由于异常启动子超甲基化。考虑到 RASSF1A 控制的大多数信号通路在靶向治疗耐药性黑色素瘤中发现发生改变，RASSF1A 缺失可能与几种 MAPK 抑制耐药机制有关。在此，我们详细讨论了耐药机制以及 RASSF1A 再激活使 BRAF 突变黑色素瘤重新对治疗敏感的潜在作用。
