MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale

Salgia, Ravi

doi:10.1158/1535-7163.mct-16-0472

Cited by 134 publications

(102 citation statements)

References 87 publications

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“…Likewise, an HGF neutralizing antibody did not affect basal cMet activation or Plk1 inhibition-induced cMet inhibition in the mesenchymal NSCLC cell line Calu6. In a second mesenchymal NSCLC cell line (H1792), the HGF neutralizing antibody did reduce basal cMet activation consistent with cancer cell production of HGF leading to cMet activation that has previously been well established in some NSCLC tumors (Salgia, 2017). In H1792 cells, the combination of the HGF neutralizing antibody and Plk1 inhibition had an additive effect on cMet activation ( Fig EV5B).…”

Section: Plk1 Inhibition or Silencing Decreases Vimentin Phosphorylatsupporting

confidence: 80%

Non‐canonical cM et regulation by vimentin mediates Plk1 inhibitor–induced apoptosis

et al. 2019

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To address the need for improved systemic therapy for non–small‐cell lung cancer ( NSCLC ), we previously demonstrated that mesenchymal NSCLC was sensitive to polo‐like kinase (Plk1) inhibitors, but the mechanisms of resistance in epithelial NSCLC remain unknown. Here, we show that cM et was differentially regulated in isogenic pairs of epithelial and mesenchymal cell lines. Plk1 inhibition inhibits cM et phosphorylation only in mesenchymal cells. Constitutively active cM et abrogates Plk1 inhibitor–induced apoptosis. Likewise, cM et silencing or inhibition enhances Plk1 inhibitor–induced apoptosis. Cells with acquired resistance to Plk1 inhibitors are more epithelial than their parental cells and maintain cM et activation after Plk1 inhibition. In four animal NSCLC models, mesenchymal tumors were more sensitive to Plk1 inhibition alone than were epithelial tumors. The combination of cM et and Plk1 inhibition led to regression of tumors that did not regrow when drug treatment was stopped. Plk1 inhibition did not affect HGF levels but did decrease vimentin phosphorylation, which regulates cM et phosphorylation via β1‐integrin. This research defines a heretofore unknown mechanism of ligand‐independent activation of cM et downstream of Plk1 and an effective combination therapy.

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Section: Plk1 Inhibition or Silencing Decreases Vimentin Phosphorylatsupporting

confidence: 80%

Non‐canonical cM et regulation by vimentin mediates Plk1 inhibitor–induced apoptosis

et al. 2019

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“…Overexpression of other members of group B, including MST1R, MET, FGFR1, TYRO3, TEC, and ABL1, influenced signaling dynamics of p-ERK1/2 and p-90RSK in a manner similar to that of EGFR overexpression ( Figure 4A). These proteins correspond to the global cluster 1 ( Figure S4B), and members of this class mediate oncogenic signaling for many cancer types (Duan et al, 2016;Paul and Mukhopadhyay, 2004;Salgia, 2017). Taken together, this suggests that ligand-independent MAPK/ERK signaling activation causes uncontrolled cell proliferation.…”

mentioning

confidence: 80%

Analysis of the human kinome and phosphatome reveals diseased signaling networks induced by overexpression

Lun

Szklarczyk

Gábor

et al. 2018

Preprint

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Kinase and phosphatase overexpression drives tumorigenesis and drug resistance in many cancer types. Signaling networks reprogrammed by protein overexpression remain largely uncharacterized, hindering discovery of paths to therapeutic intervention. We previously developed a single cell proteomics approach based on mass cytometry that enables quantitative assessment of overexpression effects on the signaling network. Here we applied this approach in a human kinome-and phosphatome-wide study to assess how 649 individually overexpressed proteins modulate the cancer-related signaling network in HEK293T cells. Based on these data we expanded the functional classification of human kinases and phosphatases and detected 208 novel signaling relationships. In the signaling dynamics analysis, we showed that increased ERK-specific phosphatases sustained proliferative signaling, and using a novel combinatorial overexpression approach, we confirmed this phosphatase-driven mechanism of cancer progression. Finally, we identified 54 proteins that caused ligand-independent ERK activation with potential as biomarkers for drug resistance in cells carrying BRAF mutations.

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“…Mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase that belongs to the MET (MNNG HOS transforming gene) family (Salgia, 2017). C-Met is encoded by the human MET gene, located on chromosome 7 (bands q21-q31) (Liu, 1998).…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs and Long Non-coding RNAs in c-Met-Regulated Cancers

Zhan

Zhang

et al. 2020

Front. Cell Dev. Biol.

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MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are components of many signaling pathways associated with tumor aggressiveness and cancer metastasis. Some lncRNAs are classified as competitive endogenous RNAs (ceRNAs) that bind to specific miRNAs to prevent interaction with target mRNAs. Studies have shown that the hepatocyte growth factor/mesenchymal-epithelial transition factor (HGF/c-Met) pathway is involved in physiological and pathological processes such as cell growth, angiogenesis, and embryogenesis. Overexpression of c-Met can lead to sustained activation of downstream signals, resulting in carcinogenesis, metastasis, and resistance to targeted therapies. In this review, we evaluated the effects of anti-oncogenic and oncogenic non-coding RNAs (ncRNAs) on c-Met, and the interactions among lncRNAs, miRNAs, and c-Met in cancer using clinical and tissue chromatin immunoprecipition (ChIP) analysis data. We summarized current knowledge of the mechanisms and effects of the lncRNAs/miR-34a/c-Met axis in various tumor types, and evaluated the potential therapeutic value of lncRNAs and/or miRNAs targeted to c-Met on drug-resistance. Furthermore, we discussed the functions of lncRNAs and miRNAs in c-Met-related carcinogenesis and potential therapeutic strategies.

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MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale

Cited by 134 publications

References 87 publications

Non‐canonical cM et regulation by vimentin mediates Plk1 inhibitor–induced apoptosis

Non‐canonical cM et regulation by vimentin mediates Plk1 inhibitor–induced apoptosis

Analysis of the human kinome and phosphatome reveals diseased signaling networks induced by overexpression

MicroRNAs and Long Non-coding RNAs in c-Met-Regulated Cancers

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