Pharmacological Targeting of Casein Kinase 1δ Suppresses Oncogenic NRAS-Driven Melanoma

Activating mutations in NRAS account for 20-30% of melanoma, yet effective anti-NRAS therapies are still lacking. In this study, we unveil the casein kinase 1δ (CK1δ) as an uncharacterized regulator of oncogenic NRAS mutations, specifically Q61R and Q61K, which are the most prevalent NRAS mutations in melanoma. The genetic ablation or pharmacological inhibition of CK1δ markedly destabilizes NRAS mutants and suppresses their oncogenic functions. Moreover, we identify USP46 as a bona fide deubiquitinase of NRAS mutants. Mechanistically, CK1δ directly phosphorylates USP46 and activates its deubiquitinase activity towards NRAS mutants, thus promoting oncogenic NRAS-driven melanocyte malignant transformation and melanoma progression in vitro and in vivo. Our findings underscore the significance of the CK1δ-USP46 axis in stabilizing oncogenic NRAS mutants and provide preclinical evidence that targeting this axis holds promise as a therapeutic strategy for human melanoma harboring NRAS mutations.

NRAS基因的激活突变约占黑色素瘤病例的20%~30%，但目前仍缺乏有效的抗NRAS治疗方案。本研究揭示了酪蛋白激酶1δ（casein kinase 1δ，CK1δ）作为致癌性NRAS突变——尤其是黑色素瘤中最常见的NRAS突变Q61R与Q61K——的未被表征的调控因子。通过基因敲除或药物抑制CK1δ，可显著降低NRAS突变体的稳定性并抑制其致癌功能。此外，本研究鉴定USP46为NRAS突变体的确切去泛素化酶。机制层面，CK1δ可直接磷酸化USP46并激活其对NRAS突变体的去泛素化酶活性，从而在体外与体内促进致癌NRAS驱动的黑素细胞恶性转化及黑色素瘤进展。本研究结果凸显了CK1δ-USP46轴在稳定致癌性NRAS突变体中的关键意义，并为靶向该轴作为携带NRAS突变的人类黑色素瘤的治疗策略提供了临床前证据。