Association of constitutively activated hepatocyte growth factor receptor (Met) with resistance to a dual EGFR/Her2 inhibitor in non-small-cell lung cancer cells

Agarwal, Seema; Zerillo, Cynthia; Kolmakova, Julia; Christensen, James G.; Harris, Lyndsay; Rimm, David L.; DiGiovanna, Michael P.; Stern, David F.

doi:10.1038/sj.bjc.6604937

Cited by 88 publications

(69 citation statements)

References 34 publications

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“…In non-small cell lung cancer cells, MET overexpression increases EGFR downstream signaling, and the combined use of dual EGFR/HER2 and MET tyrosine kinase inhibitors results in maximal growth inhibition. 43 Conversely, Qi et al 44 have reported that resistance to MET kinase inhibitors in gastric cancer cells develops via activation of the EGFR pathway. In a recent tumor-xenograft study, simultaneous targeting of MET and EGFR pathways provided synergistic inhibitory effects in breast, lung and pancreatic cancers.…”

Section: Discussionmentioning

confidence: 99%

MET is a potential target for use in combination therapy with EGFR inhibition in triple-negative/basal-like breast cancer

et al. 2013

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MET, a cell surface receptor for hepatocyte growth factor, is involved in the development of triple-negative/basal-like breast cancer (TNBC/BLBC). However, its utility as a therapeutic target in this subtype of breast cancer is poorly understood. To evaluate MET fully as a potential therapeutic target for TNBC/BLBC, we investigated the relationship between MET expression and clinical outcomes of patients with breast cancer and the functional effect of MET inhibition. Using automated immunohistochemistry (Ventana), we analyzed MET expression in 924 breast cancer patients with relevant clinicopathologic parameters. BLBC showed the strongest relationship with MET expression (57.5%, p < 0.001). High expression of MET in breast cancer resulted in poor overall survival (p 5 0.001) and disease-free survival (DFS, p 5 0.010). MET expression was relatively high in TNBC cell lines, and the silencing of MET via small interfering RNA reduced cell proliferation and migration. We observed reduced TNBC cell viability after treatment with the MET inhibitor PHA-665752. In the most drug-resistant cell line, MDA-MB-468, which showed elevated epidermal growth factor receptor (EGFR) expression, silencing of EGFR resulted in increased sensitivity to PHA-665752 treatment. We confirmed that PHA-665752 synergizes with the EGFR inhibitor erlotinib to decrease the viability of MDA-MB-468 cells. TNBC patients coexpressing MET and EGFR showed significantly worse DFS than that in patients expressing EGFR alone (p 5 0.021). Our findings strongly suggest that MET may be a therapeutic target in TNBC and that the combined therapy targeting MET and EGFR may be beneficial for the treatment of TNBC/BLBC patients.

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Section: Discussionmentioning

confidence: 99%

MET is a potential target for use in combination therapy with EGFR inhibition in triple-negative/basal-like breast cancer

et al. 2013

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“…MET was reported to interact with both EGFR and HER2. 36 These results suggest that cross talk between the EGFR pathway and the MET pathway might occur in Group I cell lines, and that co-activation of EGFR and MET might be associated with genetic abnormalities of EGFR, MET, and HER2. Ϫ6 mol/L) suppressed the expressions and phosphorylation of both EGFR and MET in HCC827 and Calu-3.…”

Section: Hierarchical Cluster Analysis Of Cell Linesmentioning

confidence: 75%

Co-Activation of Epidermal Growth Factor Receptor and c-MET Defines a Distinct Subset of Lung Adenocarcinomas

Matsubara

Ishikawa

Oguni

et al. 2010

The American Journal of Pathology

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Epidermal growth factor receptor (EGFR) and MET are molecular targets for lung cancer treatment. The relationships between expression, activation, and gene abnormalities of these two targets are currently unclear. Here, we demonstrate that a panel of 40 lung cancer cell lines could be classified into two groups. Group I was characterized by (1) high phosphorylations of MET and EGFR, (2) frequent mutation or amplification of EGFR, MET, and human epidermal growth factor receptor-2 (HER2), (3) high expressions of bronchial epithelial markers (thyroid transcription factor-1 (TTF-1), MUC1, and Cytokeratin 7 (CK7)); and (4) high expressions of MET, human epidermal growth factor receptor-3, E-cadherin, cyclooxygenase-2, and laminin gamma2. In contrast, Group II exhibited little or no phosphorylation of MET and EGFR; no mutation or amplification of EGFR, MET, and HER2; were triple-negative for TTF-1, MUC1, and CK7; and showed high expressions of vimentin, fibroblast growth factor receptor-1, and transcription factor 8. Importantly, Group I was more sensitive to gefitinib and more resistant to cisplatin and paclitaxel than Group II. The clinical relevance was confirmed in publicly available data on 442 primary lung adenocarcinoma patients; survival benefits by postoperative chemotherapy were seen in only patients with tumors corresponding to Group II. Overall, co-activation of EGFR and MET defines a distinct subgroup of lung carcinoma with characteristic genetic abnormalities, gene expression pattern , and response to chemotherapeutic reagents. (Am J

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“…Prolonged Met signaling most probably constitutes the tumor-promoting properties of HGF, which include, in addition to invasion, cellular proliferation, survival, actin remodeling and motility (Birchmeier et al, 2003;Gentile et al, 2008). Met overexpression and activating mutations are strongly associated with aggressive cancers, including carcinomas of breast, prostate, lung, brain, gastric and pancreatic origin (Agarwal et al, 2009;Sawada et al, 2007;Taniguchi et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

HGF-induced invasion by prostate tumor cells requires anterograde lysosome trafficking and activity of Na+-H+ exchangers

Steffan

Williams

Welbourne

et al. 2010

Journal of Cell Science

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SummaryHepatocyte growth factor (HGF) is found in tumor microenvironments, and interaction with its tyrosine kinase receptor Met triggers cell invasion and metastasis. It was previously shown that acidic extracellular pH stimulated peripheral lysosome trafficking, resulting in increased cathepsin B secretion and tumor cell invasion, which was dependent upon sodium-proton exchanger (NHE) activity. We now demonstrate that HGF induced the trafficking of lysosomes to the cell periphery, independent of HGF-induced epithelialmesenchymal transition. HGF-induced anterograde lysosome trafficking depended upon the PI3K pathway, microtubules and RhoA, resulting in increased cathepsin B secretion and invasion by the cells. HGF-induced NHE activity via increased net acid production, and inhibition of NHE activity with 5-(N-ethyl-N-isopropyl)-amiloride (EIPA), or a combination of the NHE1-specific drug cariporide and the NHE3-specific drug s3226 prevented HGF-induced anterograde trafficking and induced retrograde trafficking in HGFoverexpressing cells. EIPA treatment reduced cathepsin B secretion and HGF-induced invasion by the tumor cells. Lysosomes were located more peripherally in Rab7-shRNA-expressing cells and these cells were more invasive than control cells. Overexpression of the Rab7 effector protein, RILP, resulted in a juxtanuclear location of lysosomes and reduced HGF-induced invasion. Together, these results suggest that the location of lysosomes is an inherently important aspect of invasion by tumor cells.

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Association of constitutively activated hepatocyte growth factor receptor (Met) with resistance to a dual EGFR/Her2 inhibitor in non-small-cell lung cancer cells

Cited by 88 publications

References 34 publications

MET is a potential target for use in combination therapy with EGFR inhibition in triple-negative/basal-like breast cancer

MET is a potential target for use in combination therapy with EGFR inhibition in triple-negative/basal-like breast cancer

Co-Activation of Epidermal Growth Factor Receptor and c-MET Defines a Distinct Subset of Lung Adenocarcinomas

HGF-induced invasion by prostate tumor cells requires anterograde lysosome trafficking and activity of Na+-H+ exchangers

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