Vachtenheim Jiri, Ondrušová Lubica
Department of Transcription and Cell Signaling, Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University Prague, Katerinska 32, 12108 Prague, Czech Republic.
Life (Basel). 2021 May 5;11(5):424. doi: 10.3390/life11050424.
Advanced melanoma is a relentless tumor with a high metastatic potential. The combat of melanoma by using the targeted therapy is impeded because several major driver mutations fuel its growth (predominantly and ). Both these mutated oncogenes strongly activate the MAPK (MEK/ERK) pathway. Therefore, specific inhibitors of these oncoproteins or MAPK pathway components or their combination have been used for tumor eradication. After a good initial response, resistant cells develop almost universally and need the drug for further expansion. Multiple mechanisms, sometimes very distant from the MAPK pathway, are responsible for the development of resistance. Here, we review many of the mechanisms causing resistance and leading to the dismal final outcome of mutated and therapy. Very heterogeneous events lead to drug resistance. Due to this, each individual mechanism would be in fact needed to be determined for a personalized therapy to treat patients more efficiently and causally according to molecular findings. This procedure is practically impossible in the clinic. Other approaches are therefore needed, such as combined treatment with more drugs simultaneously from the beginning of the therapy. This could eradicate tumor cells more rapidly and greatly diminish the possibility of emerging mechanisms that allow the evolution of drug resistance.
晚期黑色素瘤是一种具有高转移潜能的侵袭性肿瘤。由于几种主要的驱动突变促进其生长（主要是 和 ），使用靶向治疗对抗黑色素瘤受到阻碍。这两种突变的致癌基因均强烈激活MAPK（MEK/ERK）通路。因此，这些癌蛋白或MAPK通路成分的特异性抑制剂或其组合已被用于根除肿瘤。在取得良好的初始反应后，几乎普遍会出现耐药细胞，并且需要药物来进一步增殖。多种机制，有时与MAPK通路相距甚远，导致耐药性的产生。在此，我们综述了许多导致耐药并导致突变 和 治疗最终结果不佳的机制。非常异质性的事件导致耐药。因此，实际上需要确定每种个体机制，以便根据分子发现更有效且有针对性地进行个性化治疗来治疗患者。这种方法在临床上几乎是不可能的。因此需要其他方法，例如从治疗开始就同时联合使用更多药物。这可以更迅速地根除肿瘤细胞，并大大降低出现允许耐药性演变的机制的可能性。
