RON<i>(MST1R)</i>is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma

Catenacci, Daniel V.T.; Cervantes, Gustavo M.; Yala, Soheil; Nelson, Erik A.; El-Hashani, Essam; Kanteti, Rajani; Dinali, Mohamed El; Hasina, Rifat; Brägelmann, Johannes; Seiwert, Tanguy Y.; Sanicola, Michele; Henderson, Les; Grushko, Tatyana A.; Olopade, Olufunmilayo I.; Karrison, Theodore; Bang, Yung Jue; Kim, Woo Ho; Tretiakova, Maria; Vokes, Everett E.; Frank, David A.; Kindler, Hedy L.; Huet, Heather; Salgia, Ravi

doi:10.4161/cbt.12.1.15747

Cited by 78 publications

(120 citation statements)

References 80 publications

(102 reference statements)

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“…This degradation is unlikely due to HGF, as we observed no HGF expression in MKN45 as measured by qPCR and by ELISA of the conditioned media (data not shown). The lack of HGF expression in MKN45 is consistent with one report (39) but conflicts with another report (40). This discord among reports may be due to different sources of the MKN45 cells.…”

Section: Evaluation Of Ly2875358 In Monkeycontrasting

confidence: 41%

LY2875358, a Neutralizing and Internalizing Anti-MET Bivalent Antibody, Inhibits HGF-Dependent and HGF-Independent MET Activation and Tumor Growth

Liu¹,

Zeng²,

Wortinger³

et al. 2014

Clinical Cancer Research

121

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Purpose: MET, the receptor for hepatocyte growth factor (HGF), has been implicated in driving tumor proliferation and metastasis. High MET expression is correlated with poor prognosis in multiple cancers. Activation of MET can be induced either by HGF-independent mechanisms such as gene amplification, specific genetic mutations, and transcriptional upregulation or by HGF-dependent autocrine or paracrine mechanisms.Experimental Design/Results: Here, we report on LY2875358, a novel humanized bivalent anti-MET antibody that has high neutralization and internalization activities, resulting in inhibition of both HGFdependent and HGF-independent MET pathway activation and tumor growth. In contrast to other bivalent MET antibodies, LY2875358 exhibits no functional agonist activity and does not stimulate biologic activities such as cell proliferation, scattering, invasion, tubulogenesis, or apoptosis protection in various HGFresponsive cells and no evidence of inducing proliferation in vivo in a monkey toxicity study. LY2875358 blocks HGF binding to MET and HGF-induced MET phosphorylation and cell proliferation. In contrast to the humanized one-armed 5D5 anti-MET antibody, LY2875358 induces internalization and degradation of MET that inhibits cell proliferation and tumor growth in models where MET is constitutively activated. Moreover, LY2875358 has potent antitumor activity in both HGF-dependent and HGF-independent (METamplified) xenograft tumor models. Together, these findings indicate that the mechanism of action of LY2875358 is different from that of the one-armed MET antibody.Conclusions: LY2875358 may provide a promising therapeutic strategy for patients whose tumors are driven by both HGF-dependent and HGF-independent MET activation. LY2875358 is currently being investigated in multiple clinical studies. Clin Cancer Res; 20(23); 6059-70. Ó2014 AACR.

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Section: Evaluation Of Ly2875358 In Monkeycontrasting

confidence: 41%

LY2875358, a Neutralizing and Internalizing Anti-MET Bivalent Antibody, Inhibits HGF-Dependent and HGF-Independent MET Activation and Tumor Growth

Liu¹,

Zeng²,

Wortinger³

et al. 2014

Clinical Cancer Research

121

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“…The activity observed supports the presumed biology and suggests there may be certain disease states in which single-agent onartuzumab could provide clinical benefit. Further studies will be required to better characterize the efficacy of onartuzumab in populations with autocrine MET, high MET, amplified MET, or even mutated MET disease (19), as well as to elucidate possible mechanisms of resistance to onartuzumab therapy, such as KRAS or RON amplification (25,26).…”

Section: Discussionmentioning

confidence: 99%

Phase I Dose-Escalation Study of Onartuzumab as a Single Agent and in Combination with Bevacizumab in Patients with Advanced Solid Malignancies

Salgia

Patel

Bothos

et al. 2014

Clinical Cancer Research

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Purpose: This first-in-human study evaluated the safety, immunogenicity, pharmacokinetics, and antitumor activity of onartuzumab, a monovalent antibody against the receptor tyrosine kinase MET.Experimental Design: This 3þ3 dose-escalation study comprised three stages: (i) phase Ia dose escalation of onartuzumab at doses of 1, 4, 10, 20, and 30 mg/kg intravenously every 3 weeks; (ii) phase Ia cohort expansion at the recommended phase II dose (RP2D) of 15 mg/kg; and (iii) phase Ib dose escalation of onartuzumab at 10 and 15 mg/kg in combination with bevacizumab (15 mg/kg intravenously every 3 weeks). Serum samples were collected for evaluation of pharmacokinetics, potential pharmacodynamic markers, and antitherapeutic antibodies.Results: Thirty-four patients with solid tumors were treated in phase Ia and 9 in phase Ib. Onartuzumab was generally well tolerated at all dose levels evaluated; the maximum tolerated dose was not reached. The most frequent drug-related adverse events included fatigue, peripheral edema, nausea, and hypoalbuminemia. In the phase Ib cohort, onartuzumab at the RP2D was combined with bevacizumab and no doselimiting toxicities were seen. Onartuzumab showed linear pharmacokinetics in the dose range from 4 to 30 mg/kg. The half-life was approximately 8 to 12 days. There were no apparent pharmacokinetic interactions between onartuzumab and bevacizumab, and antitherapeutic antibodies did not seem to affect the safety or pharmacokinetics of onartuzumab. A patient with gastric carcinoma in the 20-mg/kg dose cohort achieved a durable complete response for nearly 2 years.Conclusions: Onartuzumab was generally well tolerated as a single agent and in combination with bevacizumab in patients with solid tumors. Clin Cancer Res; 20(6); 1666-75. Ó2014 AACR.

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“…36,37 Expression of MST1R is also associated with unfavorable clinical outcomes [38][39][40] or not associated with prognosis. 41 However, a recent study found that MET expression is associated with a favorable prognosis in cHL.…”

Section: Discussionmentioning

confidence: 99%

“…54,55 Amplification, mutation, and overexpression of the MST1R have also been reported in renal and lung cancer and implicated in transformation, tumor formation, and metastasis. 39,56 Furthermore, amplification of 3p, which is a the chromosome region containing MST1R, is a common event in lung, renal, and breast cancer, occurring in 15-42.5% of the samples examined. 57 MET signaling is mainly mediated by the RAS-MAPK and PI3K-AKT pathways and affects gene expression and cell cycle progression.…”

Section: Discussionmentioning

confidence: 99%

MET and MST1R as prognostic factors for classical Hodgkin's lymphoma

et al. 2013

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MST1R (RON) and MET are receptor tyrosine kinase gene family members that form a noncovalent complex on the cell surface, a critical step in tumor progression. A recent study suggested a prognostic role of MET expression in Hodgkin/Reed-Sternberg (HRS) cells in classical Hodgkin's lymphoma (cHL). The purpose of this study was to examine the prognostic significance of MET and MST1R expression in cHL. The prognostic impact of MET and MST1R was examined in 100 patients with cHL (median age: 32 years) by immunohistochemistry and mRNA in situ hybridization. The median follow-up time was 95 months (interquartile range: 42-126 months). MET or MST1R protein expression was associated with high MET or MST1R mRNA expression, respectively. Thirty-eight patients (38%) expressed MET protein in HRS cell, which was associated with better overall survival (P ¼ 0.004). Twenty-six patients (26%) expressed MST1R protein, which was associated with better overall survival (P ¼ 0.022) and event-free survival (P ¼ 0.021). Multivariate analysis identified MET protein as an independent prognostic factor for overall survival and MST1R protein as an independent prognostic factor for event-free survival. Subgroup analysis according to Ann Arbor stage showed that expressions of MET and MST1R protein have prognostic impact in the advanced stage only. In particular, coexpression of MST1R and MET protein was associated with a better survival outcome than MET or MST1R expression alone or no expression. This study suggests that MET and MST1R are independent prognostic factors in classical cHL, and may allow the identification of a subgroup of cHL patients who require more intensive therapy.

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RON(MST1R)is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma

Cited by 78 publications

References 80 publications

LY2875358, a Neutralizing and Internalizing Anti-MET Bivalent Antibody, Inhibits HGF-Dependent and HGF-Independent MET Activation and Tumor Growth

LY2875358, a Neutralizing and Internalizing Anti-MET Bivalent Antibody, Inhibits HGF-Dependent and HGF-Independent MET Activation and Tumor Growth

Phase I Dose-Escalation Study of Onartuzumab as a Single Agent and in Combination with Bevacizumab in Patients with Advanced Solid Malignancies

MET and MST1R as prognostic factors for classical Hodgkin's lymphoma

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