Tiago Manoela, Purwin Timothy J, Stefanski Casey D, da Silva Renaira Oliveira, Fane Mitchell E, Chhabra Yash, Haj Jelan I, Teh Jessica Lf, Kadamb Rama, Cai Weijia, Rosenbaum Sheera R, Chua Vivian, Hacohen Nir, Davies Michael A, Villanueva Jessie, Chervoneva Inna, Weeraratna Ashani T, Erkes Dan A, Capparelli Claudia, Aguirre-Ghiso Julio A, Aplin Andrew E
Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Department of Clinical Chemistry and Toxicology, University of São Paulo, São Paulo, Brazil.
J Clin Invest. 2025 Jul 29;135(18). doi: 10.1172/JCI178446. eCollection 2025 Sep 16.
Despite the success of targeted inhibitors in cutaneous melanoma, therapeutic responses are limited by the aged tumor microenvironment and drug-tolerant residual cells. Given the similarities between drug tolerance and cellular dormancy, we studied the dormancy marker, nuclear receptor subfamily 2 group F member 1 (NR2F1), in response to BRAF-V600E inhibitors (BRAFi) plus MEK inhibitors (MEKi) in BRAF-mutant melanoma models. Transcriptomic analysis of melanoma patient samples treated with BRAFi + MEKi showed increased NR2F1. NR2F1 was highly expressed in the drug-tolerant invasive cell state of minimal residual disease in patient-derived and mouse-derived xenografts on BRAFi + MEKi. NR2F1 over-expression was sufficient to reduce BRAFi + MEKi effects on tumor growth in vivo, and cell proliferation, death, and invasion in vitro. Effects were linked to genes involved in mTORC1 signaling. These cells were sensitive to the combination of BRAFi, MEKi plus rapamycin. Melanomas from aged mice, known to exhibit decreased responses to BRAFi + MEKi, displayed higher levels of NR2F1 compared to tumors from young mice. Depleting NR2F1 in an aged mouse melanomas improved the response to targeted therapy. These findings show high NR2F1 expression in 'invasive-state' residual cells and that targeting NR2F1-high cells with mTORC1 inhibitors may improve outcomes in patients with melanoma.
尽管靶向抑制剂在皮肤黑色素瘤治疗中取得了成功，但治疗反应受到老化的肿瘤微环境和耐药性残留细胞的限制。鉴于药物耐受性与细胞休眠之间的相似性，我们在BRAF突变黑色素瘤模型中研究了休眠标志物核受体亚家族2组F成员1（NR2F1）对BRAF-V600E抑制剂（BRAFi）加MEK抑制剂（MEKi）的反应。对接受BRAFi + MEKi治疗的黑色素瘤患者样本进行转录组分析显示NR2F1增加。在BRAFi + MEKi治疗的患者来源和小鼠来源异种移植瘤的微小残留病的耐药性侵袭细胞状态中，NR2F1高度表达。NR2F1过表达足以降低BRAFi + MEKi对体内肿瘤生长以及体外细胞增殖、死亡和侵袭的影响。这些影响与mTORC1信号通路相关的基因有关。这些细胞对BRAFi、MEKi加雷帕霉素的联合治疗敏感。已知对BRAFi + MEKi反应降低的老年小鼠黑色素瘤与年轻小鼠的肿瘤相比，NR2F1水平更高。在老年小鼠黑色素瘤中消耗NR2F1可改善对靶向治疗的反应。这些发现表明“侵袭状态”残留细胞中NR2F1高表达，并且用mTORC1抑制剂靶向NR2F1高表达细胞可能改善黑色素瘤患者的治疗结果。
