The Efficacy and Risk Profile of c-Met inhibitors in Non-small Cell Lung Cancer: a Meta-analysis

Ye, Sa; Li, Jiuke; Hao, Ke; Yan, Jianping; Zhou, Hongbin

doi:10.1038/srep35770

Cited by 16 publications

(14 citation statements)

References 39 publications

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“…Although the overexpression of MET protein is associated with poor prognosis in lung cancer, it was less effective as a predictive biomarker for targeted therapeutic efficacy. 78 Previous studies have found that MET overexpression has higher sensitivity and negative predictive value; 49,79 however, due to the significant intratumoral heterogeneity, immunohistochemical evaluation of MET overexpression remains challenging, limiting its use as a biomarker in the clinic. 80,81 This difficulty in screening patients for MET-targeted therapy may also partly explain the failure of MET inhibitors in recent phase III clinical trials of NSCLC.…”

Section: Overexpression Of Met/p-metmentioning

confidence: 99%

<p>MET Oncogene in Non-Small Cell Lung Cancer: Mechanism of MET Dysregulation and Agents Targeting the HGF/c-Met Axis</p>

Liang¹,

Wang²

2020

OTT

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Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide and has a poor prognosis. Current treatments for advanced NSCLC included traditional chemotherapy, radiotherapy, targeted therapy, and immunotherapy. The efficacy of targeted therapy relies on oncogene addiction. Mesenchymal-epithelial transition factor (MET) gene can encode unconventional receptor tyrosine kinases with pleiotropic functions, when signals are abnormally activated, it can initiate and maintain tumor transformation, promote cell proliferation, survival, tumor invasion and angiogenesis. Thus, it is a promising therapeutic target. Previous studies have shown that elevated levels of HGF and/or overexpression of c-Met are associated with poor prognosis in lung cancer. In preclinical and clinical trials, c-MET inhibitors have shown some antitumor activity in NSCLC. Although the efficacy results of MET inhibitors in Phase III clinical trials are disappointing, given the molecular heterogeneity of NSCLC, only subgroups of patients with MET gene alterations may benefit from c-MET inhibitors. The challenge for the future is to screen out the potential beneficiaries. To solve this problem, there is need for large data analysis for the detection methods and treatment effects, to establish standards that meet the MET activation status, and determine reliable thresholds to achieve effective patient stratification and clinical decision making. This article summarized the structure of the hepatocyte growth factor (HGF)/c-Met axis, the different mechanisms of MET addiction, as well as MET amplification as acquired resistance mechanism to epidermal growth factor receptor-tyrosine kinase inhibitors, the latest advances of MET inhibitors, and immuotherapy in the treatment of NSCLC with MET alterations.

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Section: Overexpression Of Met/p-metmentioning

confidence: 99%

<p>MET Oncogene in Non-Small Cell Lung Cancer: Mechanism of MET Dysregulation and Agents Targeting the HGF/c-Met Axis</p>

Liang¹,

Wang²

2020

OTT

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“…Several MET TKI and MET specific antibodies have entered clinical trials [79,114]. However, based on preclinical data, acquired resistance to MET kinase inhibitors is likely to occur rapidly in cancer patients as well.…”

Section: Hgf/met Signaling Is a Hallmark Of Therapeutic Resistancementioning

confidence: 99%

Hepatocyte Growth Factor, a Key Tumor-Promoting Factor in the Tumor Microenvironment

Owusu

Galemmo²,

Janetka

et al. 2017

Cancers

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The tumor microenvironment plays a key role in tumor development and progression. Stromal cells secrete growth factors, cytokines and extracellular matrix proteins which promote growth, survival and metastatic spread of cancer cells. Fibroblasts are the predominant constituent of the tumor stroma and Hepatocyte Growth Factor (HGF), the specific ligand for the tyrosine kinase receptor c-MET, is a major component of their secretome. Indeed, cancer-associated fibroblasts have been shown to promote growth, survival and migration of cancer cells in an HGF-dependent manner. Fibroblasts also confer resistance to anti-cancer therapy through HGF-induced epithelial mesenchymal transition (EMT) and activation of pro-survival signaling pathways such as ERK and AKT in tumor cells. Constitutive HGF/MET signaling in cancer cells is associated with increased tumor aggressiveness and predicts poor outcome in cancer patients. Due to its role in tumor progression and therapeutic resistance, both HGF and MET have emerged as valid therapeutic targets. Several inhibitors of MET and HGF are currently being tested in clinical trials. Preclinical data provide a strong indication that inhibitors of HGF/MET signaling overcome both primary and acquired resistance to EGFR, HER2, and BRAF targeting agents. These findings support the notion that co-targeting of cancer cells and stromal cells is required to prevent therapeutic resistance and to increase the overall survival rate of cancer patients. HGF dependence has emerged as a hallmark of therapeutic resistance, suggesting that inhibitors of biological activity of HGF should be included into therapeutic regimens of cancer patients.

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“…In a meta-analysis, targeting c-MET therapies has been found to improve progression-free survival (PFS) and disease control rate (DCR) in advanced or metastatic NSCLC patients. However, c-MET inhibitors did not show the therapeutic benefits on their overall survival and objective response rate (Ye et al, 2016). It would be interesting to analyze the impact of cigarette smoke on the therapeutic efficacy of c-MET inhibitor in NSCLC patients.…”

Section: Discussionmentioning

confidence: 99%

Cigarette smoke enhances oncogene addiction to c‐MET and desensitizes EGFR‐expressing non‐small cell lung cancer to EGFR TKIs

Cheng

Chen

et al. 2018

Molecular Oncology

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Cigarette smoking is one of the leading risks for lung cancer and is associated with the insensitivity of non‐small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, it remains undetermined whether and how cigarette smoke affects the therapeutic efficacy of EGFR TKIs. In this study, our data showed that chronic exposure to cigarette smoke extract (CSE) or tobacco smoke‐derived carcinogen benzo[α]pyrene, B[α]P, but not nicotine‐derived nitrosamine ketone (NNK), reduced the sensitivity of wild‐type EGFR‐expressing NSCLC cells to EGFR TKIs. Treatment with TKIs almost abolished EGFR tyrosine kinase activity but did not show an inhibitory effect on downstream Akt and ERK pathways in B[α]P‐treated NSCLC cells. CSE and B[α]P transcriptionally upregulate c‐MET and activate its downstream Akt pathway, which is not inhibited by EGFR TKIs. Silencing of c‐MET reduces B[α]P‐induced Akt activation. The CSE‐treated NSCLC cells are sensitive to the c‐MET inhibitor crizotinib. These findings suggest that cigarette smoke augments oncogene addiction to c‐MET in NSCLC cells and that MET inhibitors may show clinical benefits for lung cancer patients with a smoking history.

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The Efficacy and Risk Profile of c-Met inhibitors in Non-small Cell Lung Cancer: a Meta-analysis

Cited by 16 publications

References 39 publications

<p>MET Oncogene in Non-Small Cell Lung Cancer: Mechanism of MET Dysregulation and Agents Targeting the HGF/c-Met Axis</p>

<p>MET Oncogene in Non-Small Cell Lung Cancer: Mechanism of MET Dysregulation and Agents Targeting the HGF/c-Met Axis</p>

Hepatocyte Growth Factor, a Key Tumor-Promoting Factor in the Tumor Microenvironment

Cigarette smoke enhances oncogene addiction to c‐MET and desensitizes EGFR‐expressing non‐small cell lung cancer to EGFR TKIs

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