Lipchick Brittany, Guterres Adam N, Chen Hsin-Yi, Zundell Delaine M, Del Aguila Segundo, Reyes-Uribe Patricia I, Tirado Yulissa, Basu Subhasree, Yin Xiangfan, Kossenkov Andrew V, Lu Yiling, Mills Gordon B, Liu Qin, Goldman Aaron R, Murphy Maureen E, Speicher David W, Villanueva Jessie
Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA 19104, USA.
Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Sci Transl Med. 2025 Feb 5;17(784):eadp8913. doi: 10.1126/scitranslmed.adp8913.
Although oncogenic NRAS activates mitogen-activated protein kinase (MAPK) signaling, inhibition of the MAPK pathway is not therapeutically efficacious in -mutant () tumors. Here, we report that selectively silencing the ribosomal protein S6 kinase 2 (S6K2) while preserving the activity of S6K1 perturbs lipid metabolism, enhances fatty acid unsaturation, and triggers lethal lipid peroxidation in melanoma cells that are resistant to MAPK inhibition. S6K2 depletion induces endoplasmic reticulum stress and peroxisome proliferator-activated receptor α (PPARα) activation, triggering cell death selectively in MAPK inhibitor-resistant melanoma. We found that combining PPARα agonists and polyunsaturated fatty acids phenocopied the effects of S6K2 abrogation, blocking tumor growth in both patient-derived xenografts and immunocompetent murine melanoma models. Collectively, our study establishes S6K2 and its effector subnetwork as promising targets for melanomas that are resistant to global MAPK pathway inhibitors.
尽管致癌性NRAS激活丝裂原活化蛋白激酶（MAPK）信号通路，但抑制MAPK途径在NRAS突变（NRASmut）肿瘤中并无治疗效果。在此，我们报告，在保留S6K1活性的同时选择性沉默核糖体蛋白S6激酶2（S6K2），会扰乱脂质代谢，增强脂肪酸不饱和度，并在对MAPK抑制有抗性的黑色素瘤细胞中引发致命的脂质过氧化。S6K2缺失会诱导内质网应激和过氧化物酶体增殖物激活受体α（PPARα）活化，从而在对MAPK抑制剂有抗性的黑色素瘤中选择性引发细胞死亡。我们发现，将PPARα激动剂和多不饱和脂肪酸联合使用可模拟S6K2缺失的效果，在患者来源的异种移植瘤和具有免疫活性的小鼠黑色素瘤模型中均能阻断肿瘤生长。总的来说，我们的研究表明S6K2及其效应子网络是对整体MAPK途径抑制剂有抗性的黑色素瘤的有前景的靶点。
