Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.
Department of Private Ophthalmic Practice in Cooperation with the Skin Cancer Unit, University Hospital of Zurich, Zurich, Switzerland.
Oncologist. 2020 Nov;25(11):e1593-e1597. doi: 10.1634/theoncologist.2019-0656. Epub 2020 Sep 21.
Melanoma can be classified based on the detection of relevant oncogenic driver mutations. These mutations partially determine a patient's treatment options. MEK inhibitors have demonstrated little efficacy in patients with NRAS-mutated melanoma owing to primary and secondary resistance. We report two patients with NRAS-mutant metastatic melanoma with long-term response to intermittent MEK-inhibitor binimetinib therapy. Intermittent dosing schedules could play a key role in preventing resistance to targeted therapy. This article highlights the efficacy of an intermittent dosing schedule, toxicities associated with binimetinib, and possible mechanisms preventing resistance in targeted therapy. Intermittent MEK-inhibitor therapy may be considered in patients with NRAS-mutated melanoma that have failed all standard therapies. KEY POINTS: Melanomas harbor NRAS mutations in 10%-30% of the cases. These mutations promote hyperactivation of the MAPK pathway, leading to proliferation and prolonged survival of tumor cells. Currently, drugs directly targeting NRAS are not available. Downstream inhibition of the MAPK pathway can be considered as a therapeutic option after immunotherapeutic failure. Intermittent administration of kinase inhibitors might be the way to partially overcome the development of drug resistance by (a) inducing a fitness deficit for drug-resistant cells on treatment break, (b) increasing the immunogenicity, and (c) inducing apoptosis and cell cycle arrest. It also enhances expression of numerous immunomodulating molecules, and reduction of immunosuppressive factors, which suggests better access of the immune system to the tumor.
黑色素瘤可以基于相关致癌驱动突变的检测进行分类。这些突变部分决定了患者的治疗选择。由于原发和继发耐药性，MEK 抑制剂在NRAS 突变型黑色素瘤患者中的疗效甚微。我们报告了两例NRAS 突变型转移性黑色素瘤患者，他们对间歇性 MEK 抑制剂比美替尼治疗有长期反应。间歇性给药方案可能在预防靶向治疗耐药性方面发挥关键作用。本文强调了间歇性给药方案的疗效、比美替尼相关的毒性以及在靶向治疗中预防耐药性的可能机制。对于所有标准治疗均失败的NRAS 突变型黑色素瘤患者，可以考虑间歇性 MEK 抑制剂治疗。要点：NRAS 突变在 10%-30%的黑色素瘤病例中存在。这些突变促进 MAPK 通路的过度激活，导致肿瘤细胞的增殖和存活时间延长。目前，直接针对 NRAS 的药物不可用。MAPK 通路的下游抑制可作为免疫治疗失败后的一种治疗选择。激酶抑制剂的间歇性给药可能通过以下方式部分克服耐药性的发展：（a）在治疗中断时使耐药细胞产生适应性缺陷，（b）增加免疫原性，（c）诱导细胞凋亡和细胞周期停滞。它还增强了许多免疫调节分子的表达，并减少了免疫抑制因子的表达，这表明免疫系统更容易进入肿瘤。
