Early-Stage Lung Adenocarcinoma MDM2 Genomic Amplification Predicts Clinical Outcome and Response to Targeted Therapy.
Early-Stage Lung Adenocarcinoma MDM2 Genomic Amplification Predicts Clinical Outcome and Response to Targeted Therapy.
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DOI：
10.3390/cancers14030708
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发表时间：
2022-01-29
期刊：
影响因子：
5.2
通讯作者：
Powell CA
中科院分区：
文献类型：
--
作者：
Sinha A;Zou Y;Patel AS;Yoo S;Jiang F;Sato T;Kong R;Watanabe H;Zhu J;Massion PP;Borczuk AC;Powell CA
肺腺癌（LUAD）的侵袭性亚型显示MDM 2扩增，这与较差的生存率相关。小鼠双微体2（MDM 2）在肺腺癌（LUAD）中经常扩增，是p53的负调节因子，与p53结合并调节其活性和稳定性。MDM 2的基因组扩增和过表达以及p53的遗传改变导致LUAD的基因组和遗传异质性，LUAD代表治疗靶点。在一组LUAD细胞系中的体外测定显示，肿瘤细胞对MDM 2靶向治疗的反应与MDM 2扩增相关。肺癌是男性和女性癌症相关死亡的最常见原因，占全球癌症相关死亡率的四分之一。肺腺癌是非小细胞肺癌（NSCLC）的主要亚型，约占肺癌病例的40%。肺腺癌是一种高度异质性的疾病，患者通常表现出不同的组织病理学形态，遗传改变和基因组畸变。包括我们小组在内的研究人员在肺腺癌转录组学和遗传学分析方面的最新进展，为这种异质性疾病提供了更好的分层，这有助于设计适合于靶向患者队列的更好治疗策略。在最近的一项研究中，我们发现基因表达谱鉴定了早期LUAD患者的新聚集，并与肿瘤侵袭性和患者生存率相关。在这项研究中，我们专注于LUAD患者的拷贝数改变。SNP阵列数据鉴定了MDM 2基因座上染色体12 q15处的扩增和LUAD患者亚类中具有侵袭性疾病亚型的蛋白质过表达。高拷贝数扩增和蛋白质表达在这个亚类与总生存率差。我们假设MDM 2拷贝数和过表达预测对MDM 2靶向治疗的反应。一组LUAD细胞的体外功能数据显示，MDM 2靶向治疗有效抑制了MDM 2扩增/过表达细胞的细胞增殖、迁移和侵袭，但在无MDM 2扩增的细胞中则不然，与p53状态无关。为了确定关键的信号传导机制，我们使用RNA测序（RNA seq）来检查MDM 2扩增/过表达p53突变体和野生型LUAD细胞对治疗的反应。RNA测序数据显示，在MDM 2扩增/过表达的p53野生型条件下，E2 F → PEG 10 → MMPs通路是有效的，而在p53突变遗传背景下，MDM 2靶向治疗通过抑制上皮向间充质转化（EMT）信号传导消除LUAD细胞中的肿瘤进展。我们的研究提供了一种潜在的临床相关策略，选择LUAD患者进行MDM 2靶向治疗，可能会提高缓解率，从而提高生存率。
Invasive subtypes of lung adenocarcinoma (LUAD) show MDM2 amplification that is associated with poor survival. Mouse double minute 2 (MDM2) is frequently amplified in lung adenocarcinoma (LUAD) and is a negative regulator of p53, which binds to p53 and regulates its activity and stability. Genomic amplification and overexpression of MDM2, together with genetic alterations in p53, leads to genomic and genetic heterogeneity in LUAD that represents a therapeutic target. In vitro assays in a panel of LUAD cell lines showed that tumor cell response to MDM2-targeted therapy is associated with MDM2 amplification. Lung cancer is the most common cause of cancer-related deaths in both men and women, accounting for one-quarter of total cancer-related mortality globally. Lung adenocarcinoma is the major subtype of non-small cell lung cancer (NSCLC) and accounts for around 40% of lung cancer cases. Lung adenocarcinoma is a highly heterogeneous disease and patients often display variable histopathological morphology, genetic alterations, and genomic aberrations. Recent advances in transcriptomic and genetic profiling of lung adenocarcinoma by investigators, including our group, has provided better stratification of this heterogeneous disease, which can facilitate devising better treatment strategies suitable for targeted patient cohorts. In a recent study we have shown gene expression profiling identified novel clustering of early stage LUAD patients and correlated with tumor invasiveness and patient survival. In this study, we focused on copy number alterations in LUAD patients. SNP array data identified amplification at chromosome 12q15 on MDM2 locus and protein overexpression in a subclass of LUAD patients with an invasive subtype of the disease. High copy number amplification and protein expression in this subclass correlated with poor overall survival. We hypothesized that MDM2 copy number and overexpression predict response to MDM2-targeted therapy. In vitro functional data on a panel of LUAD cells showed that MDM2-targeted therapy effectively suppresses cell proliferation, migration, and invasion in cells with MDM2 amplification/overexpression but not in cells without MDM2 amplification, independent of p53 status. To determine the key signaling mechanisms, we used RNA sequencing (RNA seq) to examine the response to therapy in MDM2-amplified/overexpressing p53 mutant and wild-type LUAD cells. RNA seq data shows that in MDM2-amplified/overexpression with p53 wild-type condition, the E2F → PEG10 → MMPs pathway is operative, while in p53 mutant genetic background, MDM2-targeted therapy abrogates tumor progression in LUAD cells by suppressing epithelial to mesenchymal transition (EMT) signaling. Our study provides a potentially clinically relevant strategy of selecting LUAD patients for MDM2-targeted therapy that may provide for increased response rates and, thus, better survival.
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影响因子：
8.3
作者：
Forma E;Jóźwiak P;Bryś M;Krześlak A
通讯作者：
Krześlak A
E2F-1诱导的PEG10过表达促进胰腺癌细胞增殖、迁移和侵袭
DOI：
10.1186/s13046-017-0500-x
发表时间：
2017-02-13
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Peng YP;Zhu Y;Yin LD;Zhang JJ;Wei JS;Liu X;Liu XC;Gao WT;Jiang KR;Miao Y
通讯作者：
Miao Y
影响因子：
7.5
作者：
Günther, T;Schneider-Stock, R;Roessner, A
通讯作者：
Roessner, A
影响因子：
4.2
作者：
Michalk, Maike;Meinrath, Jeannine;Odenthal, Margarete
通讯作者：
Odenthal, Margarete
影响因子：
4.6
作者：
Kato S;Ross JS;Gay L;Dayyani F;Roszik J;Subbiah V;Kurzrock R
通讯作者：
Kurzrock R