Dual inhibition of MAPK and TORC1 signaling retards development of radiation resistance in pediatric BRAFV600E glioma models.

IF 13.4 1区 医学 Q1 CLINICAL NEUROLOGY
Fuyang Li, Kathryn M Bondra, Hanzhou Wang, Dias Kurmashev, Bipasha Mukherjee, Suman Kanji, Amyn A Habib, Yidong Chen, Siyuan Zheng, Sandeep Burma, Peter J Houghton
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引用次数: 0

Abstract

Background: MAPK pathway inhibitors (MAPKi) have shown significant efficacy in treating childhood BRAF-activated brain tumors. For tumors harboring BRAFV600E mutations, the drugs are rarely curative, and patients can become refractory to treatment. MAPKi combining X-radiation therapy (XRT) may improve cure rate, but the development of XRT resistance is a challenge.

Methods: XRT resistance was induced by multiple XRT cycles in pediatric BRAFV600E glioma patient-derived xenograft (PDX) models. RNA sequencing was performed to identify differentially expressed genes and pathways potentially contributing to XRT resistance. Cells isolated from PDXs were used to test the contribution of specific genes and pathways to XRT resistance. PDX models were used to evaluate the efficacy of targeted treatments combined with XRT.

Results: Tumors developed resistance after multiple cycles of XRT. MEK inhibition combining XRT significantly improved tumor control compared to XRT alone, but resistance to combined therapy developed rapidly. RNA sequencing analysis revealed up-regulation of MAPK and PI3K-mTOR signaling in the XRT-resistant tumors. Isolated cells showed in vitro resistance to XRT, which was partially reversed by inhibiting PI3K-mTOR. Up-regulation of TORC1 signaling in XRT naïve tumor cells, via constitutively active Akt or TSC2 deletion, conferred in vitro XRT resistance. The pro-survival gene BIRC5 (Survivin), a target of TORC1 signaling, contributed to XRT resistance. Combining trametinib-rapamycin with XRT significantly enhanced therapeutic efficacy in PDX models and prevented or delayed resistance development.

Conclusion: PI3K-mTOR activation promotes the development of XRT resistance in pediatric BRAFV600E glioma. Dual targeting of MAPK and TORC1 signaling significantly enhances the therapeutic efficacy of XRT and can potentially prevent the development of XRT resistance.

MAPK和TORC1信号的双重抑制延缓儿童BRAFV600E胶质瘤模型放射耐药的发展
背景:MAPK通路抑制剂(MAPKi)在治疗儿童braf激活的脑肿瘤中显示出显著的疗效。对于携带BRAFV600E突变的肿瘤,这些药物几乎无法治愈,患者可能难以治疗。MAPKi联合x射线治疗(XRT)可能提高治愈率,但XRT耐药性的发展是一个挑战。方法:在儿童BRAFV600E胶质瘤患者来源的异种移植(PDX)模型中,多次XRT周期诱导XRT耐药。进行RNA测序以鉴定可能导致xrt耐药的差异表达基因和途径。从pdx分离的细胞被用来测试特定基因和途径对xrt抗性的贡献。采用PDX模型评价靶向治疗联合XRT的疗效。结果:多周期XRT治疗后肿瘤出现耐药。与单独XRT相比,MEK抑制联合XRT显著改善了肿瘤控制,但对联合治疗的耐药性迅速发展。rna测序分析显示,在xrt耐药肿瘤中,MAPK和PI3K-mTOR信号表达上调。分离的细胞显示出XRT的体外抗性,通过抑制PI3K-mTOR部分逆转。XRT naïve肿瘤细胞中TORC1信号的上调,通过组成性活性AKT或TSC2缺失,赋予XRT体外抗性。促生存基因BIRC5 (Survivin)是TORC1信号传导的靶标,有助于xrt耐药。曲美替尼-雷帕霉素联合XRT显著提高了PDX模型的治疗效果,并预防或延迟了耐药性的发展。结论:PI3K-mTOR激活促进了儿童BRAFV600E胶质瘤xrt耐药的发展。双重靶向MAPK和TORC1信号可显著提高XRT的治疗效果,并可能阻止XRT耐药的发生。(250字)。
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
Neuro-oncology
Neuro-oncology 医学-临床神经学
CiteScore
27.20
自引率
6.30%
发文量
1434
审稿时长
3-8 weeks
期刊介绍: Neuro-Oncology, the official journal of the Society for Neuro-Oncology, has been published monthly since January 2010. Affiliated with the Japan Society for Neuro-Oncology and the European Association of Neuro-Oncology, it is a global leader in the field. The journal is committed to swiftly disseminating high-quality information across all areas of neuro-oncology. It features peer-reviewed articles, reviews, symposia on various topics, abstracts from annual meetings, and updates from neuro-oncology societies worldwide.
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