Background/Objectives:Neurofibromatosis type 1 (NF1) is a prevalent inherited disorder, with approximately 50% of affected individuals developing plexiform neurofibromas (PNFs), which can progress to highly aggressive malignant peripheral nerve sheath tumors (MPNSTs). While selumetinib is FDA-approved for PNFs, its efficacy in MPNSTs is limited and associated with dose-limiting toxicities.NF1deficiency drives tumorigenesis and alters immune dynamics via RAS hyperactivation. Given the substantial macrophage infiltration in NF1 lesions and its association with disease progression, we hypothesized that targeting tumor-promoting immune cells with the retinoid X receptor (RXR) agonist MSU-42011 could be an alternative therapeutic strategy, as it has shown promise in KRAS-driven cancers by decreasing pERK levels and reducing tumor-promoting immune cells.Methods:We examined the effects of MSU-42011 and selumetinib, alone and in combination, on NF1-deficient cells and in a syngeneic MPNST model.Results:In vivo, the combination of MSU-42011 and selumetinib significantly reduced tumor growth, pERK levels, and tumor-promoting macrophages and increased activated CD8+T cells in syngeneic MPNST models. In NF1-deficient cells, MSU-42011 or selumetinib reduced pERK levels, with combination treatment achieving greater reductions. Conditioned media (CM) from NF1-deficient cells increased the protein and mRNA levels of several cytokines and chemokines in human THP1 cells and bone marrow-derived macrophages (BMDMs). MSU-42011 and selumetinib, alone or in combination, partially reversed this induction.Conclusions:These findings suggest RXR agonists may have therapeutic potential against NF1, and their combination with MEK inhibitors could represent a promising strategy for NF1-associated tumors. Further studies are needed to validate these results and assess their translational relevance.
**背景/目的：** 1型神经纤维瘤病（NF1）是一种常见的遗传性疾病，约50%的患者会发展为丛状神经纤维瘤（PNFs），并可进展为高度侵袭性的恶性外周神经鞘瘤（MPNSTs）。尽管司美替尼（selumetinib）已获FDA批准用于治疗PNFs，但其对MPNSTs的疗效有限且存在剂量限制性毒性。NF1缺失通过RAS过度激活驱动肿瘤发生并改变免疫动态。鉴于NF1病变中存在大量巨噬细胞浸润且与疾病进展相关，我们假设靶向促肿瘤免疫细胞可能成为一种替代治疗策略。维甲酸X受体（RXR）激动剂MSU-42011在KRAS驱动的癌症中显示出通过降低pERK水平和减少促肿瘤免疫细胞发挥作用的潜力，因此我们探讨其治疗NF1的可能性。 **方法：** 我们在NF1缺陷细胞及同系MPNST模型中检测了MSU-42011和司美替尼单药及联合使用的效果。 **结果：** 在体内同系MPNST模型中，MSU-42011与司美替尼联合治疗显著抑制了肿瘤生长、降低pERK水平、减少促肿瘤巨噬细胞并增加活化的CD8⁺ T细胞。在NF1缺陷细胞中，MSU-42011或司美替尼单药均能降低pERK水平，而联合治疗效果更显著。NF1缺陷细胞的条件培养基（CM）可提升人THP1细胞和骨髓来源巨噬细胞（BMDMs）中多种细胞因子和趋化因子的蛋白及mRNA水平，MSU-42011和司美替尼单药或联合使用可部分逆转这一诱导效应。 **结论：** 这些结果表明RXR激动剂可能对NF1具有治疗潜力，且与MEK抑制剂联用或可成为NF1相关肿瘤的有前景的治疗策略。仍需进一步研究验证这些结果并评估其临床转化意义。
The RXR Agonist MSU-42011 Reduces Tumor Burden in a Murine Preclinical NF1-Deficient Model
肿瘤(癌症)患者之家