Linking FOXM1 and PD-L1 to CDK4/6-MEK targeted therapy resistance in malignant peripheral nerve sheath tumors.

Q2 Medicine
Joshua J Lingo, Ellen Voigt, Dawn E Quelle
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引用次数: 0

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, Ras-driven sarcomas characterized by loss of the NF1 tumor suppressor gene and hyperactivation of MEK and CDK4/6 kinases. MPNSTs lack effective therapies. We recently demonstrated remarkable efficacy of dual CDK4/6-MEK inhibition in mice with de novo MPNSTs, which was heightened by combined targeting of the immune checkpoint protein, PD-L1. The triple combination therapy targeting CDK4/6, MEK, and PD-L1 led to extended MPNST regression and improved survival, although most tumors eventually acquired drug resistance. Here, we consider the immune activation phenotype caused by CDK4/6-MEK inhibition in MPNSTs that uniquely involved intratumoral plasma cell accumulation. We discuss how PD-L1 and FOXM1, a tumor-promoting transcription factor, are functionally linked and may be key mediators of resistance to CDK4/6-MEK targeted therapies. Finally, the role of FOXM1 in suppressing anti-tumor immunity and potentially thwarting immune-based therapies is considered. We suggest that future therapeutic strategies targeting the oncogenic network of CDK4/6, MEK, PD-L1, and FOXM1 represent exciting future treatment options for MPNST patients.

将 FOXM1 和 PD-L1 与恶性周围神经鞘瘤的 CDK4/6-MEK 靶向治疗耐药性联系起来。
恶性周围神经鞘瘤(MPNSTs)是一种侵袭性 Ras 驱动肉瘤,其特征是 NF1 抑癌基因缺失以及 MEK 和 CDK4/6 激酶过度激活。MPNST 缺乏有效的治疗方法。最近,我们在患有新发 MPNST 的小鼠中证实了 CDK4/6-MEK 双抑制的显著疗效,而联合靶向免疫检查点蛋白 PD-L1 则增强了疗效。针对CDK4/6、MEK和PD-L1的三联疗法延长了MPNST的消退时间并提高了生存率,尽管大多数肿瘤最终会产生耐药性。在此,我们探讨了 CDK4/6-MEK 抑制在 MPNST 中引起的免疫激活表型,这种表型独特地涉及瘤内浆细胞聚集。我们讨论了 PD-L1 和 FOXM1(一种肿瘤促进转录因子)如何在功能上相互关联,并可能成为 CDK4/6-MEK 靶向疗法耐药性的关键介质。最后,我们还考虑了 FOXM1 在抑制抗肿瘤免疫和可能挫败基于免疫的疗法中的作用。我们认为,针对 CDK4/6、MEK、PD-L1 和 FOXM1 等致癌网络的未来治疗策略是未来治疗 MPNST 患者的令人兴奋的选择。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Oncotarget
Oncotarget Oncogenes-CELL BIOLOGY
CiteScore
6.60
自引率
0.00%
发文量
129
审稿时长
1.5 months
期刊介绍: Information not localized
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