Preclinical Evaluation of AMG 337, a Highly Selective Small Molecule MET Inhibitor, in Hepatocellular Carcinoma

Du, Zhiqiang; Caenepeel, Sean; Shen, Yuqing; Rex, Karen; Zhang, Yanni; He, Ying; Tang, En-Tzu; Wang, Ouhong; Zhong, Wenge; Zhou, Hui; Huang, Jacqueline; Huang, L. Eric; Hu, Liaoyuan A.; Coxon, Angela; Zhang, Mingqiang

doi:10.1158/1535-7163.mct-15-0745

Cited by 16 publications

(14 citation statements)

References 33 publications

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“…To relate our analysis of HER3/MET interactions in the COS7 cell model system of MET overexpression to a physiological scenario of MET amplification, we used a hepatocellular carcinoma cell line, MHCC97-H, in which genomic MET is amplified approximately 15-fold. 43, 44 MET protein levels in these cells are ~ 2 fold higher than overexpression of MET that is achieved by transient transfection of MET in our COS7 cell model system (Fig. 1e and Supplementary Fig.…”

Section: Resultsmentioning

confidence: 74%

Overexpression-mediated activation of MET in the Golgi promotes HER3/ERBB3 phosphorylation

et al. 2018

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Ligand-dependent oligomerization of receptor tyrosine kinases (RTKs) results in their activation through highly specific conformational changes in the extracellular and intracellular receptor domains. These conformational changes are unique for each RTK sub-family, limiting cross-activation between unrelated RTKs. The proto-oncogene MET receptor tyrosine kinase overcomes these structural constraints and phosphorylates unrelated RTKs in numerous cancer cell lines. The molecular basis for these interactions is unknown. We investigated the mechanism by which MET phosphorylates the human epidermal growth factor receptor-3 (HER3 or ERBB3), a catalytically impaired RTK whose phosphorylation by MET has been described as an essential component of drug resistance to inhibitors targeting EGFR and HER2. We find that in untransformed cells, HER3 is not phosphorylated by MET in response to ligand stimulation, but rather to increasing levels of MET expression, which results in MET activation in a ligand-independent manner. Phosphorylation of HER3 by its canonical dimerization partners, EGFR and HER2, is achieved by engaging an allosteric site on the HER3 kinase domain, but this site is not required when HER3 is phosphorylated by MET. We also observe that HER3 preferentially interacts with MET during its maturation along the secretory pathway, before MET is post-translationally processed by cleavage within its extracellular domain. This results in accumulation of phosphorylated HER3 in the Golgi apparatus. We further show that in addition to HER3, MET phosphorylates other RTKs in the Golgi, suggesting that this mechanism is not limited to HER3 phosphorylation. These data demonstrate a link between MET overexpression and its aberrant activation in the Golgi endomembranes and suggest that non-canonical interactions between MET and unrelated RTKs occur during maturation of receptors. Our study highlights a novel aspect of MET signaling in cancer that would not be accessible to inhibition by therapeutic antibodies.

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Section: Resultsmentioning

confidence: 74%

Overexpression-mediated activation of MET in the Golgi promotes HER3/ERBB3 phosphorylation

et al. 2018

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“…Selective c‐Met TKIs represent the current most likely clinical candidates. Studies of agents such as PHA665752, AMG 337, RP1400, and tepotinib both in vitro and in vivo provide consistent evidence that selective targeting of c‐Met can inhibit the proliferation of HCC cells and cause xenograft tumors to shrink, with effects greatest when c‐Met expression is high . Effects on cell motility and migration have also been observed.…”

Section: Selective C‐met Inhibitorsmentioning

confidence: 82%

Recent developments of c‐Met as a therapeutic target in hepatocellular carcinoma

et al. 2018

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Aberrant c‐Met activity has been implicated in the development of hepatocellular carcinoma (HCC), suggesting that c‐Met inhibition may have therapeutic potential. However, clinical trials of nonselective kinase inhibitors with c‐Met activity (tivantinib, cabozantinib, foretinib, and golvatinib) in patients with HCC have failed so far to demonstrate significant efficacy. This lack of observed efficacy is likely due to several factors, including trial design, lack of patient selection according to tumor c‐Met status, and the prevalent off‐target activity of these agents, which may indicate that c‐Met inhibition is incomplete. In contrast, selective c‐Met inhibitors (tepotinib, capmatinib) can be dosed at a level predicted to achieve complete inhibition of tumor c‐Met activity. Moreover, results from early trials can be used to optimize the design of clinical trials of these agents. Preliminary results suggest that selective c‐Met inhibitors have antitumor activity in HCC, with acceptable safety and tolerability in patients with Child‐Pugh A liver function. Ongoing trials have been designed to assess the efficacy and safety of selective c‐Met inhibition compared with standard therapy in patients with HCC that were selected based on tumor c‐Met status. Thus, c‐Met inhibition continues to be an active area of research in HCC, with well‐designed trials in progress to investigate the benefit of selective c‐Met inhibitors. (Hepatology 2018;67:1132–1149)

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“…MET amplification and HGF expression are associated with capmatinib sensitivity in vitro MET gene amplification, leading to overexpression and autophosphorylation of the MET protein, has been linked to MET inhibitor sensitivity in cell lines (16)(17)(18)(19). In addition, response to capmatinib has also been reported in two preclinical models that express both MET and its ligand HGF (10).…”

Section: High Selectivity Of Capmatinib Is Explained By Its Binding Mmentioning

confidence: 99%

Capmatinib (INC280) Is Active Against Models of Non–Small Cell Lung Cancer and Other Cancer Types with Defined Mechanisms of MET Activation

Baltschukat

Engstler

Huang³

et al. 2019

Clinical Cancer Research

115

101

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Purpose: The selective MET inhibitor capmatinib is being investigated in multiple clinical trials, both as a single agent and in combination. Here, we describe the preclinical data of capmatinib, which supported the clinical biomarker strategy for rational patient selection. Experimental Design: The selectivity and cellular activity of capmatinib were assessed in large cellular screening panels. Antitumor efficacy was quantified in a large set of cell line-or patient-derived xenograft models, testing single-agent or combination treatment depending on the genomic profile of the respective models. Results: Capmatinib was found to be highly selective for MET over other kinases. It was active against cancer models that are characterized by MET amplification, marked MET overexpression, MET exon 14 skipping mutations, or MET activation via expression of the ligand hepatocyte growth factor (HGF). In cancer models where MET is the dominant oncogenic driver, anticancer activity could be further enhanced by combination treatments, for example, by the addition of apoptosis-inducing BH3 mimetics. The combinations of capmatinib and other kinase inhibitors resulted in enhanced anticancer activity against models where MET activation cooccurred with other oncogenic drivers, for example EGFR activating mutations. Conclusions: Activity of capmatinib in preclinical models is associated with a small number of plausible genomic features. The low fraction of cancer models that respond to capmatinib as a single agent suggests that the implementation of patient selection strategies based on these biomarkers is critical for clinical development. Capmatinib is also a rational combination partner for other kinase inhibitors to combat MET-driven resistance.

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Preclinical Evaluation of AMG 337, a Highly Selective Small Molecule MET Inhibitor, in Hepatocellular Carcinoma

Cited by 16 publications

References 33 publications

Overexpression-mediated activation of MET in the Golgi promotes HER3/ERBB3 phosphorylation

Overexpression-mediated activation of MET in the Golgi promotes HER3/ERBB3 phosphorylation

Recent developments of c‐Met as a therapeutic target in hepatocellular carcinoma

Capmatinib (INC280) Is Active Against Models of Non–Small Cell Lung Cancer and Other Cancer Types with Defined Mechanisms of MET Activation

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