Targeting the HGF/MET Axis in Cancer Therapy: Challenges in Resistance and Opportunities for Improvement

Huang, Xing; Li, Enliang; Shen, Hang; Wang, Xun; Tang, Tianyu; Xiao-zhen, Zhang; Xu, Jian; Tang, Zengwei; Guo, Chengxiang; Bai, Xueli; Liang, Tingbo

doi:10.3389/fcell.2020.00152

Cited by 53 publications

(55 citation statements)

References 114 publications

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“…67 Resistant mutations include point mutations, increased copy number; skip mutations or alterations in exon 14 splicing site. 68,69 Examples include: MET Y1248H and MET D1246N. 70 Other mutations such as KRAS and RON mutations have been noted to bypass pathway suppression by MET inhibitors.…”

Section: Emergence Of New Mutationsmentioning

confidence: 99%

“…Hypoxia, another characteristic of the TME, significantly reduces MET phosphorylation, while maintaining downstream signaling. 69 Furthermore, HGF/MET signaling affects immune cells within the TME, such as mast cell activation by MET-α2β1 integrin, 71 and dendritic cell (DC) impairment by diminished antigen presentation through matrix-metalloproteinase MMP2-MMP9. 72 MET inhibition also limits the activity of anti-tumor neutrophils, aiding in tumor growth.…”

Section: Microenvironment Interference and Immune Regulationmentioning

confidence: 99%

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MET Inhibitors for the Treatment of Gastric Cancer: What’s Their Potential?

Darsa¹,

Sayed²,

Abdel‐Rahman³

2020

JEP

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Gastric cancer remains a disease with a dismal prognosis. Extensive efforts to find targetable disease drivers in gastric cancer were implemented to improve patient outcomes. Beyond anti-HER2 therapy, MET pathway seems to be culprit of cancer invasiveness with MET-overexpressing tumors having poorer prognosis. Tyrosine kinase inhibitors targeting the HGF/MET pathway were studied in MET-positive gastric cancer, but no substantial benefit was proven. Some patients responded in early phase trials but later developed resistance. Others failed to show any benefit at all. Etiologies of resistance may entail inappropriate patient selection with a lack of MET detection standardization, tumor alternative pathways, variable MET amplification, and genetic variation. Optimizing MET detection techniques and better understanding the MET pathway, as well as tumor bypass mechanisms, are an absolute need to devise means to overcome resistance using targeted therapy alone, or in combination with other synergistic agents to improve outcomes of patients with MET-positive GC.

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Section: Emergence Of New Mutationsmentioning

confidence: 99%

Section: Microenvironment Interference and Immune Regulationmentioning

confidence: 99%

MET Inhibitors for the Treatment of Gastric Cancer: What’s Their Potential?

Darsa¹,

Sayed²,

Abdel‐Rahman³

2020

JEP

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“…During its clinical development, it was found that while crizotinib showed initial efficacy, patients inevitably acquired resistance to the drug. Several clinical reports described secondary MET mutations as mechanisms for crizotinib resistance [115][116][117][118], see Review [119] One such report by Zhang and colleagues also discussed the case of a patient who simultaneously acquired four rare resistance mutations (G1163R, D1228H, D1228A, and Y1230H) after the development of crizotinib resistance [115].…”

Section: (Iv) Crizotinibmentioning

confidence: 99%

Targeting HGF/c-MET Axis in Pancreatic Cancer

Pothula

Goldstein

et al. 2020

IJMS

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Pancreatic cancer (pancreatic ductal adenocarcinoma (PDAC/PC)) has been an aggressive disease that is associated with early metastases. It is characterized by dense and collagenous desmoplasia/stroma, predominantly produced by pancreatic stellate cells (PSCs). PSCs interact with cancer cells as well as other stromal cells, facilitating disease progression. A candidate growth factor pathway that may mediate this interaction is the hepatocyte growth factor (HGF)/c-MET pathway. HGF is produced by PSCs and its receptor c-MET is expressed on pancreatic cancer cells and endothelial cells. The current review discusses the role of the MET/HGF axis in tumour progression and dissemination of pancreatic cancer. Therapeutic approaches that were developed targeting either the ligand (HGF) or the receptor (c-MET) have not been shown to translate well into clinical settings. We discuss a two-pronged approach of targeting both the components of this pathway to interrupt the stromal–tumour interactions, which may represent a potential therapeutic strategy to improve outcomes in PC.

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“…The influence of TIME factors was investigated through differential expression analysis and survival analysis using GEPIA. Firstly, MET (HGF receptor, traditional receptor tyrosine kinase but with a novel regulatory function in cancer immunity [31][32][33] ) was chosen as a representative TIME factor. Compared with normal tissue, the expression level of MET was downregulated in BRCA, LAML, and LGG and upregulated in 20 types of cancers including CESC, COAD, and PAAD ( Fig.…”

Section: The Prognostic Landscape Of Icps Across Multiple Cancer Typesmentioning

confidence: 99%

Genomic investigation of co-targeting tumor immune microenvironment and immune checkpoints in pan-cancer immunotherapy

et al. 2020

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Drugs that target immune checkpoints (ICPs) have become the most popular weapons in cancer immunotherapy; however, they are only beneficial for a small fraction of patients. Accumulating evidence suggests that the tumor immune microenvironment (TIME) plays a critical role in anti-cancer immunity. This study aimed to assess the potential merits and feasibility of combinational targeting ICPs and TIME in cancer immunotherapy. A total of 31 cancer type-specific datasets in TCGA were individually collected by the publicly available web servers for multiple bioinformatic analyses of ICPs and TIME factors. GEPIA was used to calculate the prognostic indexes, STRING was used to construct protein–protein interactions, cBioPortal was used for visualization and comparison of genetic alterations, and TISIDB was used to explore the correlation to tumor-infiltrating lymphocytes (TILs). Intriguingly, TIME factors were identified to have more global coverage and prognostic significance across multiple cancer types compared with ICPs, thus offering more general targetability in clinical therapy. Moreover, TIME factors showed interactive potential with ICPs, and genomic alteration of TIME factors coupled with that of ICPs, at least in pancreatic cancer. Furthermore, TIME factors were found to be significantly associated with TILs, including but not limited to pancreatic cancer. Finally, the clinical significance and translational potential of further combination therapies that incorporate both ICP inhibitors and TIME factor-targeted treatments were discussed. Together, TIME factors are promising immunotherapeutic targets, and a combination strategy of TIME factors-targeted therapies with ICP inhibitors may benefit more cancer patients in the future.

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Targeting the HGF/MET Axis in Cancer Therapy: Challenges in Resistance and Opportunities for Improvement

Cited by 53 publications

References 114 publications

<p><em>MET</em> Inhibitors for the Treatment of Gastric Cancer: What’s Their Potential?</p>

<p><em>MET</em> Inhibitors for the Treatment of Gastric Cancer: What’s Their Potential?</p>

Targeting HGF/c-MET Axis in Pancreatic Cancer

Genomic investigation of co-targeting tumor immune microenvironment and immune checkpoints in pan-cancer immunotherapy

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