Identifying and exploiting combinatorial synthetic lethality by characterizing adaptive kinome rewiring of EGFRvIII-driven glioblastoma.

IF 6.2 2区 医学 Q1 NEUROSCIENCES
Benjamin Lin, Abigail K Shelton, Erin Smithberger, Julia Ziebro, Kasey R Skinner, Ryan E Bash, Richard Kirkman, Allie Stamper, Madison Butler, Alex Flores, Steven P Angus, Michael P East, Timothy F Cloughesy, David A Nathanson, Michael E Berens, Jann N Sarkaria, Zev A Binder, Donald M O'Rourke, Timothy C Howton, Brittany N Lasseigne, Christopher D Willey, Gary L Johnson, Anita B Hjelmeland, Frank B Furnari, C Ryan Miller
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引用次数: 0

Abstract

GBM is an aggressive primary malignant brain tumor that has a poor prognosis. Molecular characterization of GBM has shown that EGFR mutations are present in over 50% of tumors. However, EGFR inhibitors have not shown clinical efficacy in contrast to other EGFR-driven neoplasms due to the unique EGFR biology found in GBM. Upfront combinatorial therapy featuring EGFR tyrosine kinase inhibitors (TKI) may overcome these challenges. To identify combinatorial drug targets within the kinome, we temporally characterized drug-induced kinome rewiring in isogenic, genetically engineered Cdkn2a-deleted mouse astrocytes expressing human EGFRvIII. We utilize RNA sequencing and multiplex inhibitor beads, coupled with mass spectrometry, to demonstrate that kinome rewiring exhibits both shared and unique kinases after acquired resistance develops to EGFR TKI, despite using models with a common genetic background. Additionally, we noted that kinases altered in the acute setting are distinct from those in acquired resistance. By identifying kinome vulnerabilities throughout the acute, dynamic drug response process, we generated a kinase signature associated with EGFR inhibition. Further molecular interrogation of signature genes revealed that drug treatment induces an unexpected increase in Cdk6 protein, but not mRNA, despite live cell imaging and transcriptomic evidence indicating decreased proliferation. Survival experiments with orthotopic allografts show that upfront combination inhibition of Cdk6, using abemaciclib, and EGFR, using neratinib, significantly prolonged median survival compared to neratinib alone. Our findings suggest that identifying and inhibiting targets with synthetic lethality in the upfront combinatorial setting is a viable approach for precision oncology and may help provide an avenue to overcome the resistance mechanisms that contributed to the failures of EGFR as a molecular target in GBM.

通过表征egfrviii驱动的胶质母细胞瘤的适应性激酶重连接,鉴定和利用组合合成致死性。
GBM是一种侵袭性原发性恶性脑肿瘤,预后较差。GBM的分子特征表明,EGFR突变存在于50%以上的肿瘤中。然而,由于在GBM中发现的独特的EGFR生物学特性,与其他EGFR驱动的肿瘤相比,EGFR抑制剂尚未显示出临床疗效。采用EGFR酪氨酸激酶抑制剂(TKI)的前期联合治疗可能克服这些挑战。为了确定基因组内的组合药物靶点,我们暂时表征了在表达人EGFRvIII的基因工程cdkn2a缺失小鼠星形胶质细胞中药物诱导的基因组重连接。我们利用RNA测序和多重抑制剂珠,结合质谱,证明尽管使用具有共同遗传背景的模型,但在对EGFR TKI产生获得性耐药后,kinome重新连接显示出共享和独特的激酶。此外,我们注意到,在急性环境中改变的激酶不同于获得性耐药。通过在急性动态药物反应过程中识别kinome脆弱性,我们生成了与EGFR抑制相关的激酶信号。对特征基因的进一步分子分析表明,尽管活细胞成像和转录组学证据表明增殖减少,但药物治疗诱导Cdk6蛋白意外增加,而不是mRNA。原位同种异体移植物的生存实验表明,与单独使用奈拉替尼相比,使用abemaciclib联合抑制Cdk6和使用奈拉替尼联合抑制EGFR可显著延长中位生存期。我们的研究结果表明,在前期组合设置中识别和抑制具有合成致死性的靶标是精确肿瘤学的一种可行方法,并可能有助于提供克服导致EGFR作为GBM分子靶标失败的耐药机制的途径。
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
Acta Neuropathologica Communications
Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine
CiteScore
11.20
自引率
2.80%
发文量
162
审稿时长
8 weeks
期刊介绍: "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.
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