Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Oncology, Cancer Genetics and Epigenetics Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Cell Rep Med. 2024 Nov 19;5(11):101818. doi: 10.1016/j.xcrm.2024.101818. Epub 2024 Nov 1.
Neurofibromin (NF1) is a negative regulator of RAS signaling, frequently mutated in cancer. NF1-mutant melanoma is a highly malignant tumor for which targeted therapies are lacking. Here, we use biochemical and pharmacological assays on patient-derived models and isogenic cell lines to identify potential pharmacologic targets, revealing that NF1-null melanomas are dependent on RAS activation and that MEK inhibition relieves ERK-dependent negative feedback, increasing RAS signaling. MEK inhibition with avutometinib abrogates the adaptive rebound in ERK signaling, but the antitumor effects are limited. However, concurrent inhibition of MEK and SOS1 abrogates ERK activation, induces cell death, and suppresses tumor growth. In contrast to the NF1-deficient setting, concurrent SOS1 and SOS2 depletion is required to completely inhibit RAS signaling in NF1 wild-type cells. In sum, our data provide a mechanistic rationale for enhancing the therapeutic efficacy of MEK inhibitors by exploiting the lower residual SOS activity in NF1-null tumor cells.
神经纤维瘤蛋白（NF1）是 RAS 信号的负调控因子，在癌症中经常发生突变。NF1 突变型黑色素瘤是一种高度恶性的肿瘤，缺乏靶向治疗方法。在这里，我们使用基于患者来源的模型和同基因细胞系的生化和药理学检测来鉴定潜在的药理靶点，结果表明 NF1 缺失型黑色素瘤依赖于 RAS 激活，而 MEK 抑制可缓解 ERK 依赖性负反馈，增加 RAS 信号。使用 avutometinib 抑制 MEK 可消除 ERK 信号的适应性反弹，但抗肿瘤作用有限。然而，同时抑制 MEK 和 SOS1 可消除 ERK 激活、诱导细胞死亡并抑制肿瘤生长。与 NF1 缺失型情况相反，在 NF1 野生型细胞中完全抑制 RAS 信号需要同时耗尽 SOS1 和 SOS2。总之，我们的数据为通过利用 NF1 缺失型肿瘤细胞中较低的残留 SOS 活性来增强 MEK 抑制剂的治疗效果提供了机制基础。
