Targeting the tumor-promoting microenvironment in MET-amplified NSCLC cells with a novel inhibitor of pro-HGF activation

Owusu, Benjamin Y.; Thomas, Shantasia; Venukadasula, Phanindra K. M.; Han, Zhenfu; Janetka, James W.; Galemmo, Robert A.; Klampfer, Lidija

doi:10.18632/oncotarget.18260

Cited by 29 publications

(30 citation statements)

References 63 publications

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“…HGF or pro-HGF-producing fibroblasts inhibit not only the response to individual treatment with a MET kinase inhibitor, but also the response to dual inhibition of EGFR and MET [119]. We demonstrated that HGF reactivates MET, EGFR and RON signaling and restores AKT, ERK and WNK1 activation in MET-inhibited cells.…”

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

confidence: 82%

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

confidence: 82%

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

Owusu

Galemmo²,

Janetka

et al. 2017

Cancers

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“…Moreover, structural analysis of the complexes of KD1 and HGF/SF‐activating proteases may have significant implications for the development of synthetic chemicals that specifically inhibit proteolytic activation of HGF/SF and MSP. To date, several promising small molecular weight compounds that specifically inhibit the HGF/SF‐activating proteases have been reported . Generation of neutralizing antibodies against these proteases may also be a useful approach.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Hepatocyte growth factor activator inhibitors (HAI‐1 and HAI‐2): Emerging key players in epithelial integrity and cancer

Kataoka

Kawaguchi

Fukushima

et al. 2018

Pathology International

129

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The growth, survival, and metabolic activities of multicellular organisms at the cellular level are regulated by intracellular signaling, systemic homeostasis and the pericellular microenvironment. Pericellular proteolysis has a crucial role in processing bioactive molecules in the microenvironment and thereby has profound effects on cellular functions. Hepatocyte growth factor activator inhibitor type 1 (HAI-1) and HAI-2 are type I transmembrane serine protease inhibitors expressed by most epithelial cells. They regulate the pericellular activities of circulating hepatocyte growth factor activator and cellular type II transmembrane serine proteases (TTSPs), proteases required for the activation of hepatocyte growth factor (HGF)/scatter factor (SF). Activated HGF/SF transduces pleiotropic signals through its receptor tyrosine kinase, MET (coded by the proto-oncogene MET), which are necessary for cellular migration, survival, growth and triggering stem cells for accelerated healing. HAI-1 and HAI-2 are also required for normal epithelial functions through regulation of TTSP-mediated activation of other proteases and protease-activated receptor 2, and also through suppressing excess degradation of epithelial junctional proteins. This review summarizes current knowledge regarding the mechanism of pericellular HGF/SF activation and highlights emerging roles of HAIs in epithelial development and integrity, as well as tumorigenesis and progression of transformed epithelial cells.

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“…Amplification of MET in lung cancer is a well-known mechanism of resistance to epidermal growth factor receptor-targeted tyrosine kinase inhibitors (EGFR-TKIs) [105][106][107]. In addition, overexpression of HGF is observed in approximately 61% of patients with EGFR-TKIs-resistant lung cancer and is known as a cause of acquired resistance [106,107].…”

Section: Discussionmentioning

confidence: 99%

“…HGF/MET signaling-induced EMT is a major phenomenon in various cancer cells [104]. Recently, it has been reported that HGF/MET signaling-induced inhibition of SMURF2 yielded stabilization of TGF-β receptor, and that upregulation of TGF-β signaling axis leads to EMT of UC cell line [105]. However, compared with PC and RCC, the function of TTSPs and HAIs in UC is not well known.…”

Section: Significance Of Hgf-dependent Met Activation In Muscle Invasmentioning

confidence: 99%

Dysregulation of Type II Transmembrane Serine Proteases and Ligand-Dependent Activation of MET in Urological Cancers

Mukai

Yamasaki

Fujisawa

et al. 2020

IJMS

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Unlike in normal epithelium, dysregulated overactivation of various proteases have been reported in cancers. Degradation of pericancerous extracellular matrix leading to cancer cell invasion by matrix metalloproteases is well known evidence. On the other hand, several cell-surface proteases, including type II transmembrane serine proteases (TTSPs), also induce progression through activation of growth factors, protease activating receptors and other proteases. Hepatocyte growth factor (HGF) known as a multifunctional growth factor that upregulates cancer cell motility, invasiveness, proliferative, and anti-apoptotic activities through phosphorylation of MET (a specific receptor of HGF). HGF secreted as inactive zymogen (pro-HGF) from cancer associated stromal fibroblasts, and the proteolytic activation by several TTSPs including matriptase and hepsin is required. The activation is strictly regulated by HGF activator inhibitors (HAIs) in physiological condition. However, downregulation is frequently observed in cancers. Indeed, overactivation of MET by upregulation of matriptase and hepsin accompanied by the downregulation of HAIs in urological cancers (prostate cancer, renal cell carcinoma, and bladder cancer) are also reported, a phenomenon observed in cancer cells with malignant phenotype, and correlated with poor prognosis. In this review, we summarized current reports focusing on TTSPs, HAIs, and MET signaling axis in urological cancers.

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Targeting the tumor-promoting microenvironment in MET-amplified NSCLC cells with a novel inhibitor of pro-HGF activation

Cited by 29 publications

References 63 publications

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

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

Hepatocyte growth factor activator inhibitors (HAI‐1 and HAI‐2): Emerging key players in epithelial integrity and cancer

Dysregulation of Type II Transmembrane Serine Proteases and Ligand-Dependent Activation of MET in Urological Cancers

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