Mamidi Narsimha, Das Swadesh K, Fisher Paul B
Department of Cellular, Molecular and Genetic Medicine.
VCU Institute of Molecular Medicine, and.
J Clin Invest. 2025 Sep 16;135(18). doi: 10.1172/JCI197764.
Cutaneous melanoma (CM) is known for its aggressive behavior, high metastatic potential, and poor prognosis. Mutations in the BRAF gene are common in CM, and patients with BRAF-mutant melanoma often respond well to combined inhibition of BRAF and MEK (BRAFi + MEKi). Although BRAFi + MEKi therapy provides clinical efficacy, the response durability is limited by persistent drug-tolerant residual cells, culminating in relapse. In this issue of the JCI, Tiago et al. confirmed that NR2F1, a dormancy-associated transcription factor, is a key determinant of therapeutic resistance in melanoma. NR2F1 expression was elevated in transcriptomic datasets from patients with minimal residual disease, and in murine and human melanoma models, NR2F1 overexpression reduced therapeutic efficacy and suppressed tumor proliferation and invasion while sustaining mechanistic target of rapamycin complex 1 (mTORC1) transcriptional regulation of relevant genes. Combining BRAFi + MEKi with the mTORC1 inhibitor rapamycin effectively targeted these resistant melanoma cells, suggesting a potential path forward for targeting NR2F1 and mTORC1 signaling in patients with CM.
皮肤黑色素瘤（CM）以其侵袭性、高转移潜能和不良预后而闻名。BRAF基因的突变在CM中很常见，BRAF突变型黑色素瘤患者通常对BRAF和MEK的联合抑制（BRAFi + MEKi）反应良好。尽管BRAFi + MEKi疗法具有临床疗效，但反应的持久性受到持续存在的耐药残留细胞的限制，最终导致复发。在本期《临床研究杂志》中，蒂亚戈等人证实，与休眠相关的转录因子NR2F1是黑色素瘤治疗耐药性的关键决定因素。在残留疾病极少的患者的转录组数据集中，NR2F1表达升高，并且在小鼠和人类黑色素瘤模型中，NR2F1过表达降低了治疗效果，抑制了肿瘤增殖和侵袭，同时维持了雷帕霉素复合物1（mTORC1）对相关基因的转录调控。将BRAFi + MEKi与mTORC1抑制剂雷帕霉素联合使用可有效靶向这些耐药黑色素瘤细胞，这为靶向CM患者的NR2F1和mTORC1信号通路提供了一条潜在的途径。
