MET Kinase Inhibitor SGX523 Synergizes with Epidermal Growth Factor Receptor Inhibitor Erlotinib in a Hepatocyte Growth Factor–Dependent Fashion to Suppress Carcinoma Growth

Zhang, Kun; Staal, Ben; Essenburg, Curt J.; Su, Yingchun; Kang, Liang; West, Richard; Kaufman, Dafna; DeKoning, Tom; Eagleson, Bryn; Buchanan, Sean G.; Woude, George F. Vande

doi:10.1158/0008-5472.can-10-0898

Cited by 73 publications

(63 citation statements)

References 21 publications

(26 reference statements)

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“…2E). However, the activation appeared weaker than that observed in other cancer models we have tested in this system (23,36), and showed little response to MET inhibitors after 3 wk of dosing. MET amplification has also been found in non-small cell lung cancer patients resistant to EGFR inhibitors (24).…”

Section: Discussioncontrasting

confidence: 62%

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Hepatocyte growth factor (HGF) autocrine activation predicts sensitivity to MET inhibition in glioblastoma

Xie

Bradley

Kang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

108

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Because oncogene MET and EGF receptor (EGFR) inhibitors are in clinical development against several types of cancer, including glioblastoma, it is important to identify predictive markers that indicate patient subgroups suitable for such therapies. We investigated in vivo glioblastoma models characterized by hepatocyte growth factor (HGF) autocrine or paracrine activation, or by MET or EGFR amplification, for their susceptibility to MET inhibitors. HGF autocrine expression correlated with high phospho-MET levels in HGF autocrine cell lines, and these lines showed high sensitivity to MET inhibition in vivo. An HGF paracrine environment may enhance glioblastoma growth in vivo but did not indicate sensitivity to MET inhibition. EGFRvIII amplification predicted sensitivity to EGFR inhibition, but in the same tumor, increased copies of MET from gains of chromosome 7 did not result in increased MET activity and did not predict sensitivity to MET inhibitors. Thus, HGF autocrine glioblastoma bears an activated MET signaling pathway that may predict sensitivity to MET inhibitors. Moreover, serum HGF levels may serve as a biomarker for the presence of autocrine tumors and their responsiveness to MET therapeutics.hepatocyte growth factor-autocrine loop | molecular marker | oncogene addiction | targeted therapy T he intrinsic ability of glioblastoma multiforme (GBM) tumor cells to invade normal brain tissue impedes complete surgical eradication and predictably results in early local recurrence and mortality. Understanding the molecular mechanisms of GBM invasiveness will lead to novel therapeutic strategies. The major signaling pathways driving GBM tumorigenesis and invasion are Ras-MAPK and AKT. Hepatocyte growth factor (HGF) binding to its receptor MET triggers this series of intracellular signaling, leading to tumor cell proliferation, invasion, survival, and angiogenesis (1-6). Aberrant MET activation can occur through numerous mechanisms, such as autocrine or paracrine stimulation, transcriptional regulation (7), ligand-independent or mutational activation (1, 8); MET amplification can be a major driver after acquired resistance to EGF receptor (EGFR) inhibitors (9), because of cross-talk with other receptor tyrosine kinase (RTK) family members.Most glioblastomas show MET overexpression, and some display HGF autocrine activation of the MET signaling pathway (10). Approximately 88% of GBM patients have an aberrant RTK/Ras-PI3K pathway activity. MET is located on chromosome 7q, and gains of chromosome 7 occur frequently in GBM. Also, though MET mutations are rare (11, 12), a high level of MET amplification is found in ∼4% of GBM tumors. Amplification of EGFR occurs in 45% of GBM tumors and could be associated with aberrant MET expression (11).HGF can also transcriptionally activate EGFR signaling in GBM cell lines (13), and EGFR variant III (EGFRvIII) can activate MET signaling (14), suggesting the importance of using a combination of MET and EGFR inhibitors in targeting GBM. EGFRvIII and MET inhibitors synergize against...

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Section: Discussioncontrasting

confidence: 62%

“…HGF paracrine activation was evaluated by comparing xenograft tumor growth with and without expression of human HGF in SCIDhgf-Tg vs. SCID mice (22,23). The HGF autocrine U87M2 and SF295SQ1 cells displayed similar tumor growth potential in both types of mice ( Fig.…”

Section: Hgf Expression and Met Phosphorylation In Glioblastoma Cell mentioning

confidence: 99%

Hepatocyte growth factor (HGF) autocrine activation predicts sensitivity to MET inhibition in glioblastoma

Xie

Bradley

Kang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

108

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“…The expression of hHGF significantly enhanced the growth of heterotopic subcutaneous xenografts derived from human MET-expressing cancer cells. This model has been invaluable for the testing of therapeutic agents in human cancer cells in the context of MET signaling (Gao et al 2006;Merchant et al 2008;Zhang et al 2010).…”

Section: Mouse Models Of Met and Hgf/sfmentioning

confidence: 99%

MET: A Critical Player in Tumorigenesis and Therapeutic Target

Graveel

Tolbert

Woude

2013

Cold Spring Harbor Perspectives in Biology

111

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Since its discovery more than 25 years ago, numerous studies have established that the MET receptor is unique among tyrosine kinases. Signaling through MET is necessary for normal development and for the progression of a wide range of human cancers. MET activation has been shown to drive numerous signaling pathways; however, it is not clear how MET signaling mediates diverse cellular responses such as motility, invasion, growth, and angiogenesis. Great strides have been made in understanding the pleotropic aspects of MET signaling using three-dimensional molecular structures, cell culture systems, human tumors, and animal models. These combined approaches have driven the development of MET-targeted therapeutics that have shown promising results in the clinic. Here we examine the unique features of MET and hepatocyte growth factor/scatter factor (HGF/SF) structure and signaling, mutational activation, genetic mouse models of MET and HGF/SF, and MET-targeted therapeutics.

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“…In an HGFoverexpressing SCID mouse model, the MET-specific TKI SGX523 partially inhibited HGF-dependent growth of lung, breast, and pancreatic tumor xenografts. Simultaneous targeting of MET and EGFR pathways with SGX523 plus erlotinib demonstrated greater antitumor activity in lung, breast, and pancreatic xenografts than single-agent treatment in this model [44].…”

Section: Met Amplification and Acquired Resistance To Egfr Inhibitorsmentioning

confidence: 84%

“…Recent studies in animal models of NSCLC using inhibitors of MET and EGFR have furthered our understanding of the interplay between the MET and EGFR signaling pathways and the possible synergistic benefits of dual inhibition of these pathways (Table 1) [39,[42][43][44][45][46][47]. For example, in multiple NSCLC xenograft models, including erlotinib-resistant xenografts, the combination of MGCD265 (a smallmolecule inhibitor of MET, VEGF receptor [VEGFR], Tie-2, and RON) with erlotinib demonstrated significantly greater antitumor activity than with either agent alone without significant added toxicity or drug-drug interactions [45].…”

Section: Met Amplification and Acquired Resistance To Egfr Inhibitorsmentioning

confidence: 99%

The Role of MET Receptor Tyrosine Kinase in Non-Small Cell Lung Cancer and Clinical Development of Targeted Anti-MET Agents

Robinson

Sandler

2013

The Oncologist

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A better understanding of the pathophysiology and evolution of non-small cell lung cancer (NSCLC) has identified a number of molecular targets and spurred development of novel targeted therapeutic agents. The MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) are implicated in tumor cell proliferation, migration, invasion, and angiogenesis in a broad spectrum of human cancers, including NSCLC. Amplification of MET has been reported in approximately 5%-22% of lung tumors with acquired resistance to small-molecule inhibitors of the epidermal growth factor receptor (EGFR). Implications for Practice: Identification of the role of the HGF-MET pathway in cancer, and specifically in non-small cell lung cancer (NSCLC) has led to the development of pharmaceutical agents targeting this pathway. In particular, MET's role in secondary resistance to EGFR-directed therapies has led to the investigation of combining MET-directed agents with erlotinib in patients with metastatic NSCLC. This article reviews the early development of MET-directed therapies as well as currently ongoing Phase III studies.We await the results of these studies, which will determine whether targeting MET in combination with EGFR is a valid clinical option in patients whose cancers progress following treatment with EGFR inhibitors.

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MET Kinase Inhibitor SGX523 Synergizes with Epidermal Growth Factor Receptor Inhibitor Erlotinib in a Hepatocyte Growth Factor–Dependent Fashion to Suppress Carcinoma Growth

Cited by 73 publications

References 21 publications

Hepatocyte growth factor (HGF) autocrine activation predicts sensitivity to MET inhibition in glioblastoma

Hepatocyte growth factor (HGF) autocrine activation predicts sensitivity to MET inhibition in glioblastoma

MET: A Critical Player in Tumorigenesis and Therapeutic Target

The Role of MET Receptor Tyrosine Kinase in Non-Small Cell Lung Cancer and Clinical Development of Targeted Anti-MET Agents

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