Department of Life Sciences and Medicine, University of Luxembourg, 6, avenue du Swing, L-4367 Belvaux, Luxembourg.
Skin Cancer Unit, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, D-68135 Mannheim, Germany.
Cancer Treat Rev. 2021 Sep;99:102238. doi: 10.1016/j.ctrv.2021.102238. Epub 2021 May 29.
Genetic alterations affecting RAS proteins are commonly found in human cancers. Roughly a fourth of melanoma patients carry activating NRAS mutations, rendering this malignancy particularly challenging to treat. Although the development of targeted as well as immunotherapies led to a substantial improvement in the overall survival of non-NRAS melanoma patients (e.g. BRAF), patients with NRAS melanomas have an overall poorer prognosis due to the high aggressiveness of RAS tumors, lack of efficient targeted therapies or rapidly emerging resistance to existing treatments. Understanding how NRAS-driven melanomas develop therapy resistance by maintaining cell cycle progression and survival is crucial to develop more effective and specific treatments for this group of melanoma patients. In this review, we provide an updated summary of currently available therapeutic options for NRAS melanoma patients with a focus on combined inhibition of MAPK signaling and CDK4/6-driven cell cycle progression and mechanisms of the inevitably developing resistance to these treatments. We conclude with an outlook on the most promising novel therapeutic approaches for melanoma patients with constitutively active NRAS. STATEMENT OF SIGNIFICANCE: An estimated 75000 patients are affected by NRAS melanoma each year and these patients still have a shorter progression-free survival than BRAF melanomas. Both intrinsic and acquired resistance occur in NRAS-driven melanomas once treated with single or combined targeted therapies involving MAPK and CDK4/6 inhibitors and/or checkpoint inhibiting immunotherapy. Oncolytic viruses, mRNA-based vaccinations, as well as targeted triple-agent therapy are promising alternatives, which could soon contribute to improved progression-free survival of the NRAS melanoma patient group.
影响 RAS 蛋白的遗传改变在人类癌症中很常见。大约四分之一的黑色素瘤患者携带激活的 NRAS 突变，使这种恶性肿瘤特别难以治疗。尽管靶向治疗和免疫疗法的发展导致非 NRAS 黑色素瘤患者的总体生存率有了显著提高（例如 BRAF），但由于 RAS 肿瘤的高度侵袭性、缺乏有效的靶向治疗或对现有治疗方法的快速出现耐药性，NRAS 黑色素瘤患者的总体预后较差。了解NRAS 驱动的黑色素瘤如何通过维持细胞周期进程和存活来产生耐药性，对于为这组黑色素瘤患者开发更有效和更特异的治疗方法至关重要。在这篇综述中，我们提供了目前针对 NRAS 黑色素瘤患者的治疗选择的最新总结，重点是联合抑制 MAPK 信号和 CDK4/6 驱动的细胞周期进程，以及这些治疗方法不可避免产生耐药性的机制。我们最后展望了针对NRAS 持续激活的黑色素瘤患者最有前途的新型治疗方法。
每年估计有 75000 名患者受到NRAS 黑色素瘤的影响，这些患者的无进展生存期仍然比 BRAF 黑色素瘤短。一旦接受涉及 MAPK 和 CDK4/6 抑制剂和/或检查点抑制免疫疗法的单一或联合靶向治疗，NRAS 驱动的黑色素瘤中就会出现内在和获得性耐药。溶瘤病毒、基于 mRNA 的疫苗接种以及靶向三联疗法是很有前途的替代方法，它们可能很快会有助于改善 NRAS 黑色素瘤患者群体的无进展生存期。
