Targeting MET in Lung Cancer: Will Expectations Finally Be MET?

The hepatocyte growth factor receptor (MET) is a potential therapeutic target in a number of cancers, including NSCLC. In NSCLC, MET pathway activation is thought to occur through a diverse set of mechanisms that influence properties affecting cancer cell survival, growth, and invasiveness. Preclinical and clinical evidence suggests a role for MET activation as both a primary oncogenic driver in subsets of lung cancer and as a secondary driver of acquired resistance to targeted therapy in other genomic subsets. In this review, we explore the biology and clinical significance behind MET proto-oncogene receptor tyrosine kinase (MET) exon 14 alterations and MET amplification in NSCLC, the role of MET amplification in the setting of acquired resistance to EGFR tyrosine kinase inhibitor therapy in EGFR-mutant NSCLC, and the history of MET pathway inhibitor drug development in NSCLC, highlighting current strategies that enrich for biomarkers likely to be predictive of response. Whereas previous trials that focused on MET pathway–directed targeted therapy in unselected or MET-overexpressing NSCLC yielded largely negative results, more recent investigations focusing on MET exon 14 alterations and MET amplification have been notable for meaningful clinical responses to MET inhibitor therapy in a substantial proportion of patients.     

Distinct MET Protein Localization Associated With MET Exon 14 Mutation Types in Patients With Non–small-cell Lung Cancer

Background

The MET gene has been recognized as a potential important therapeutic target in non–small-cell lung cancer (NSCLC). We sought to investigate the MET exon 14 mutations in a cohort of Chinese patients with NSCLC.

MET／HGF 抑制剂在肿瘤治疗中的研究进展

MET 是一种由 c-MET 原癌基因编码的蛋白产物,为肝细胞生长因子（hepatocyte growth factor,HGF）受体,位于细胞膜上,具有酪氨酸激酶活性,活化后最终引起细胞生物学行为改变,如细胞生长、细胞增殖、细胞运动和迁徙、细胞侵袭和促进凋亡。异常的 MET 表达在实体瘤和血液恶性肿瘤中广泛存在,具体的分子机制包括 MET 受体的过表达、基因扩增、基因突变或选择性剪接。随着对 MET 和HGF 基础研究的突破,目前已开发出 MET 抑制剂,包括：HGF 单克隆抗体、与 HGF 竞争性结合 MET 的配体、选择性和非选择性的 MET-TKI。部分安全有效的 MET 抑制剂也已进入了后期的临床研究,作者就 MET／HGF 在肿瘤中的作用及 MET 抑制剂的临床研究成果作一综述。     

Molecular cancer therapy: Can our expectation be MET?

Altered regulation of tyrosine kinase receptors (RTKs) is frequent in solid tumours and it is often associated with the acquisition of an aggressive phenotype. Thus, therapies targeting these receptors have been proposed as molecular approaches to treat human cancers. The MET proto-oncogene, encoding the tyrosine kinase receptor for hepatocyte growth factor (HGF), controls genetic programmes leading to cell growth, invasion and protection from apoptosis. Germ-line mutations of MET in patients affected by hereditary papillary renal carcinomas (HPRC) have provided strong genetic evidences for its role in human malignancies; moreover, constitutive activation of this receptor, as a consequence of different mechanisms such as over-expression, autocrine stimulation or point mutations, is frequent in sporadic cancers. Several strategies to block the activation of MET are under development, such as the use of tyrosine kinase inhibitors or monoclonal antibodies and some of these compounds have already been used in clinical trials. In this review, we will discuss the molecular mechanisms underlying MET involvement in tumourigenesis and present pre-clinical and clinical data obtained with compounds aimed at targeting MET in the frame of cancer therapy.     

MET 基因在非小细胞肺癌中的表达及其意义

目的：探讨间质上皮转化因子（MET）基因 mRNA 在非小细胞肺癌（NSCLC）中的表达及其与临床病理特征的关系。方法选取2011年6月—2013年11月在中国人民解放军总医院病理确诊为 NSCLC 的48例患者,所有患者均未接受术前治疗。采用分支-DNA 液相芯片技术对获取的肿瘤组织中 MET 基因 mRNA 表达水平进行检测,分析 MET 基因 mRNA 表达水平与临床病理特征的关系。结果MET 基因 mRNA 以中度表达为主,低度、中度和高度表达的比例分别为22．9％、50．0％和27．1％。MET 基因 mRNA 表达与患者病理类型（χ2＝7．183,P ＝0．020）和 TNM分期（χ2＝24．566,P ＝0．017）有关,与性别（χ2＝0．566,P ＝0．754）、年龄（χ2＝1．857,P ＝0．395）、吸烟史（χ2＝4．959,P ＝0．084）、分化程度（χ2＝5．749,P ＝0．067）、淋巴结转移（χ2＝1．631,P ＝0．442）和远处转移（χ2＝4．261,P ＝0．119）均无关。结论 MET 基因 mRNA 在 NSCLC 中更易呈现中、高度表达,而且 MET 基因可以作为判断肿瘤病理类型的生物学标志物。     

MET Amplification (MET/CEP7 Ratio ≥ 1.8) Is an Independent Poor Prognostic Marker in Patients With Treatment-naive Non–Small-cell Lung Cancer

IntroductionThe MET pathway is a promising target in patients with non–small-cell lung cancer (NSCLC). Fluorescence in situ hybridization analysis has become a standard method to detect MET amplification. However, no consensus has been reached regarding the definition of MET amplification. We aimed to find clinically meaningful cutoffs for MET amplification that could be used as a prognostic marker and/or indication for MET inhibitor therapy.Patients and MethodsWe reviewed the fluorescence in situ hybridization results of MET/CEP7 (centromere of chromosome 7) for 2260 patients with treatment-naive NSCLC from 2014 to 2019. Clinical and pathologic data were collected from the medical records. Log-rank tests and Cox proportional hazard models were used to estimate the overall survival (OS) among patients with different MET/CEP7 ratios and/or MET copy numbers.ResultsOf the 2260 patients, 130 (5.8%) had had a MET/CEP7 ratio of ≥ 1.8 and 13 (0.6%) had had a ratio of ≥ 5.0. Of these 130 patients with a MET/CEP7 ratio of ≥ 1.8, 123 (95%) also had a MET copy number of ≥ 5. In general, a higher MET copy number and higher MET/CEP7 ratio were associated with advanced tumor stage. The OS was significantly shorter when the MET copy number was ≥ 10 and/or when the MET/CEP7 ratio was ≥ 1.8. A MET/CEP7 ratio of ≥ 1.8 remained a significant hazard to OS on multivariate analysis (hazard ratio, 1.63; P = .019).ConclusionsPatients with a MET copy number of ≥ 10 and/or MET/CEP7 ratio of ≥ 1.8 showed significantly poorer survival, and a MET/CEP7 ratio of ≥ 1.8 was an independent poor prognostic factor.     

miR-34a调控肺癌EGFR耐药细胞株中MET信号通路探讨

[目地]研究肺癌耐药细胞株HCC827/GR中MET信号通路的调控,明确肺癌获得性耐药的分子机制。[方法]使用HCC827细胞[epidermal growth factor receptor（EGFR）基因19外显子缺少的肺腺癌细胞株],在此细胞的基础上培养吉非替尼耐药细胞株。检测耐药细胞株中MET的表达,并使用RT-PCR的方法检测miR-34a的表达;使用TargetScan等生物信息学软件预测miR-34a的下游靶点,并在细胞内验证miR-34a是否可以调控MET的表达。[结果]与HCC827细胞相比,HCC827/GR细胞株对吉非替尼明显耐药。在耐药HCC827/GR细胞株中,miR-34a低表达,MET高表达,而在HCC827细胞株中,miR-34a高表达,MET低表达。Target Scan生物信息学软件提示,MET是miR-34a的下游靶点之一。将携带荧光报告基团和MET 3′UTR的载体与miR-34a共转染入细胞后荧光度下降。[结论]miR-34a可能通过调控靶基因MET而参与EGFR-TKI的获得性耐药。     

Dual MET�CEGFR combinatorial inhibition against T790M-EGFR-mediated erlotinib-resistant lung cancer

Despite clinical approval of erlotinib, most advanced lung cancer patients are primary non-responders. Initial responders invariably develop secondary resistance, which can be accounted for by T790M-EGFR mutation in half of the relapses. We show that MET is highly expressed in lung cancer, often concomitantly with epidermal growth factor receptor (EGFR), including H1975 cell line. The erlotinib-resistant lung cancer cell line H1975, which expresses L858R/T790M-EGFR in-cis, was used to test for the effect of MET inhibition using the small molecule inhibitor SU11274. H1975 cells express wild-type MET, without genomic amplification (CNV=1.1). At 2 μM, SU11274 had significant in vitro pro-apoptotic effect in H1975 cells, 3.9-fold (P=0.0015) higher than erlotinib, but had no effect on the MET and EGFR-negative H520 cells. In vivo, SU11274 also induced significant tumour cytoreduction in H1975 murine xenografts in our bioluminescence molecular imaging assay. Using small-animal microPET/MRI, SU11274 treatment was found to induce an early tumour metabolic response in H1975 tumour xenografts. MET and EGFR pathways were found to exhibit collaborative signalling with receptor cross-activation, which had different patterns between wild type (A549) and L858R/T790M-EGFR (H1975). SU11274 plus erlotinib/CL-387,785 potentiated MET inhibition of downstream cell proliferative survival signalling. Knockdown studies in H1975 cells using siRNA against MET alone, EGFR alone, or both, confirmed the enhanced downstream inhibition with dual MET–EGFR signal path inhibition. Finally, in our time-lapse video-microscopy and in vivo multimodal molecular imaging studies, dual SU11274-erlotinib concurrent treatment effectively inhibited H1975 cells with enhanced abrogation of cytoskeletal functions and complete regression of the xenograft growth. Together, our results suggest that MET-based targeted inhibition using small-molecule MET inhibitor can be a potential treatment strategy for T790M-EGFR-mediated erlotinib-resistant non-small-cell lung cancer. Furthermore, optimised inhibition may be further achieved with MET inhibition in combination with erlotinib or an irreversible EGFR-TKI.     

Hypoxia-inducible factor-1α correlates with MET and metastasis in node-negative breast cancer

Summary The mechanism of tumor hypoxia promoting metastasis remains uncertain. Hypoxia-inducible factor-1α (HIF-1α) is a key mediator of the cellular response to hypoxia and binds the met promoter, resulting in increased expression of MET. In breast cancer, MET overexpression is associated with death caused by metastatic disease. Aim of this study is to investigate the role of HIF-1α in MET expression and metastasis in lymph node negative breast cancer. We recruited a homogeneous cohort of 104 patients with T_1–2N₀M₀ breast carcinoma, who had undergone primary surgery. Fifty-three patients had distant metastases and 51 patients had no evidence of disease for more than 10 years. We analyzed the expressions of HIF-1α and MET in these patients using immunohistochemistry. HIF-1α and MET were positively correlated (Spearman’s rank correlation coefficient, 0.35; P < 0.01), were independent predictors of distant metastasis (P = 0.002 and P = 0.03, respectively), and correlated with poor 10-year disease-free survival rate (P < 0.001 for both). Furthermore, co-overexpression of HIF-1α and MET was a significant independent predictor of distant metastasis (odd radio, 10.78; P < 0.001), and patients with co-overexpression had a significantly worse 10-year disease-free survival rate. The results provide evidence that tumor hypoxia promotes metastasis through the induction of MET overexpression by HIF-1α and emphasize the promising status of HIF-1α as a therapeutic target against metastasis in node-negative breast cancer.     

晚期非小细胞肺癌MET 14外显子跳跃突变的治疗新进展

间充质⁃上皮转化因子（mesenchymal⁃epithelial transition factor，MET）14外显子跳跃突变是非小细胞肺癌（non⁃small cell lung cancer，NSCLC）中继表皮生长因子受体（epidermal growth factor receptor，EGFR）、KRAS、间变性淋巴瘤激酶（anaplastic lymphoma kinase，ALK）后第4个最常见的独立致癌因素，同样也是NSCLC患者的独立预后因素。随着克唑替尼、卡马替尼、特泊替尼及沃利替尼等MET⁃酪氨酸激酶抑制剂（tyrosine kinase inhibitors，TKIs）接连获批，MET靶向治疗得到有效进展。本文就MET 14外显子跳跃突变的NSCLC患者治疗研究进展进行综述。     

EMT–MET in renal disease: Should we curb our enthusiasm?

Renal epithelial cells arise during embryogenesis by mesenchymal to epithelial transition (MET). In the context of renal diseases, these cells can switch back to a mesenchymal phenotype, in a process thus reminiscent of an epithelial-to-mesenchymal transition (EMT) in which we referred to as “Epithelial Phenotypic Changes” (EPC). The pathophysiological consequence of EPC is controversial: in particular, to what extent EPC contribute to the pool of disease-associated renal fibroblasts is very uncertain. However, there is strong evidence that EPC correlate with a poor renal outcome. EPC indeed reflect an exposure to a profibrotic environment, at an early and potentially reversible stage. Detecting EPC has potential therapeutic implications for patients prone to renal fibrosis, both as a marker of efficacy or more directly as a target. In opposition to the EMT occurring during embryogenesis, EMT in fibrosis as well as in cancer is an anarchic cellular process actually developing at the expense of the whole organ(ism).     

肉瘤样肝细胞癌中MET基因扩增与预后的相关性分析

背景与目的：肉瘤样肝细胞癌（sarcomatoid hepatocellular carcinoma,SHC）是一种罕见且高度恶性的肝脏肿瘤。MET基因异常具有肿瘤预后预测价值,以MET为靶点的抑制剂已成为晚期肿瘤治疗的重要方向,然而SHC组织中MET基因扩增状态尚不明确。探讨SHC中MET基因扩增与临床病理学因素的相关性及其预后预测价值。方法：收集2008年1月—2016年12月于复旦大学附属中山医院经病理学检查确诊的22例SHC患者资料。采用荧光原位杂交（fluorescence in situ hybridization,FISH）法检测上述患者的MET基因扩增情况,并结合临床病理学资料进行统计学分析。采用Kaplan-Meier模型分析总生存期（overall survival,OS）及无病生存期（disease-free survival,DFS）,采用log-rank检验比较生存曲线,采用多因素COX回归模型分析SHC中独立的预后因素。结果：22例SHC患者中,MET基因扩增5例（22.7%）。MET基因扩增存在异质性,主要位于分化差的梭形细胞区域（4例）。MET基因扩增的SHC患者中位OS明显短于MET阴性患者（6.8个月 vs 24.0个月,P=0.001）。SHC中具有完整肿瘤包膜的患者中位OS明显长于包膜不完整的患者（41.3个月 vs 8.5个月,P=0.001）。单灶肿瘤及中国肝癌分期（China Liver Cancer Staging,CNLC）Ⅰ期患者的中位DFS较多灶肿瘤及Ⅱ+Ⅲ+Ⅳ期患者明显延长（10.4个月 vs 3.8个月,12.4个月 vs 3.8个月,P=0.027和0.017）。MET基因扩增是SHC独立的预后因子。结论：22.7%（5/22）的SHC中存在MET基因扩增。MET基因扩增的SHC患者预后更差,是其预后的独立危险因素。该研究结果为该罕见肿瘤的治疗提供了新策略和临床依据。     

非小细胞肺癌组织MET和EGFR基因扩增与预后相关性分析

目的：探讨非小细胞肺癌（non-smfllleelllungcancer,NSCLC）患者中肝细胞生长因子受体（MET）基因和表皮生长因子受体（epidermalgrowthfactorreceptor,EGFR）基因扩增与临床病理特征及预后的关系。方法：回顾分析唐山市协和医院（48例）和唐山市人民医院（109例）2001—01—2007—01手术切除的NSCLC石蜡包埋标本157例。应用荧光原位杂交（fluorescenceinsituhybridization,FISH）检测NSCLCMET、EGFR基因扩增情况,并结合临床病理资料进行统计分析。应用SPSS16．0进行统计分析,Kaplan-Meier模型分析中住生存期（overallsurvival,0S）,Log—rank检验比较生存曲线,多因素分析采用Cox回归模型。结果：157例NSCLC患者标本中,EGFR基因扩增70例（44．6％）。EGFR基因扩增与年龄、性别、吸烟状态、组织类型和TNM分期无关,P〉0．05。157例NSCLC患者标本中,MET基因扩增25例（15．9％）。EGFR扩增患者MET扩增率为22．9％,高于无EGFR扩增患者MET扩增率10．3％,P=0．033。MET基因扩增与年龄、性别、吸烟状态、组织类型和TNM分期无关,P〉0．05。Kaplan-Meier生存分析显示,I＋Ⅱ期中位生存期为51个月,明显高于Ⅲ＋Ⅳ期中位生存期29个月,P=0．001。EGFRFISH阳性患者中位0s为33个月与EGFRFISH阴性患者中位0s39个月比较,差异无统计学意义,P=0．495。METFISH阳性患者中位0S为29个月,低于METFISH阴性患者37个月,P=0．044。患者0s与病理类型、年龄、性别和吸烟状态无相关性,P〉0．05。多因素分析显示,临床分期、MET基因扩增与OS有关（相对危险度为12．573、6．892,P值分别为0．015、0．018）。结论：临床Ⅲ＋Ⅳ期和MET基因扩增NSCLC患者预后不良,EGFR基因扩增与NSCLC患者预后无关。     

胃癌中MET的表达及与克唑替尼敏感性的关系

目的:研究间质表皮转化生长因子受体(MET)的表达与胃癌患者的临床病理特征、生存期、靶向药物克唑替尼的敏感性的关系。方法:采用免疫组化法（IHC）检测118例经手术切除的胃癌组织MET的表达，通过三维微组织块培养法（HDRA）进行克唑替尼的体外敏感性实验。结果:35.6%的胃癌患者高表达MET。MET的表达与年龄（P=0.442）、性别（P=0.237）、肿瘤部位（P=0.101）、疾病分期（P=0.229）及组织学分级（P=0.811）无关，与Lauren分型有显著相关性（P=0.000）。MET表达水平与克唑替尼的敏感性呈正相关（P=0.009）。MET高表达者和低表达者的总生存期分别为17.3月和18.1月，两者无显著性差异（P=0.989）。结论:MET表达水平与胃癌的Lauren分型相型相关，也是预测胃癌组织对克唑替尼敏感性的潜在指标。     

非小细胞肺癌中MET抑制剂的耐药机制及应对策略研究进展

MET基因是非小细胞肺癌的重要肿瘤驱动基因，针对MET 14外显子跳跃突变的靶向药物为患者带来新的治疗希望。虽然以tepotinib和沃利替尼等为代表的MET抑制剂显示出良好的抗肿瘤效果，但MET抑制剂的耐药不可避免。通过对HGF/MET信号通路的研究，不仅有助于探索MET抑制剂的耐药机制，有利于找到抑制和逆转耐药的方法，而且能够扩大新药研发的领域。初步研究显示HGF/MET信号通路抑制剂与其他药物的联合应用可能具有更大的临床应用潜力。本文就MET基因异常的特点，MET抑制剂的耐药机制和应对耐药策略进行综述，并提出MET抑制剂未来的发展方向和面临的挑战。      

维罗非尼治疗后获得性MET基因扩增肺腺癌一例

肺癌是我国最常见的恶性肿瘤之一.近几年,由于靶向治疗的研究进展,晚期非小细胞的生存期得到较大改善.常见的靶向治疗靶点有表皮生长因子受体(epidermal growth factor receptor, EGFR)、间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)和c-ros原癌基因1酪...