Abstract

BackgroundAccurate assessment of predictive biomarker expression is critical in patient selection in clinical trials or clinical practice. However, changes in biomarker expression may occur after treatment. The aim of the present study was to evaluate the effects of chemotherapy on MET expression in gastric cancer (GC).MethodsMET expression was examined immunohistochemically before and after treatment in 122 patients with unresectable or recurrent GC, and was evaluated according to H-score or the scoring criteria used in the MetMAb trial. MET gene amplification was assessed by chromogenic in situ hybridization (CISH). The antitumor effect of MET targeted therapy was investigated in human gastric cancer cells in vitro and in vivo, and the underlying molecular mechanisms were analyzed by western blot.ResultsMET expression was associated with Lauren classification as well as tumor differentiation by either scoring system. MET amplification was not associated with clinical characteristics. Of the 71 patients who had paired pre- and post-treatment tumor tissues, 28 patients (39%) were initially positive for MET expression, and 43 (61%) were negative. Twenty-five patients (35%) showed significant changes in MET expression after treatment (P=0.007). Additionally, there was a concomitant overexpression of MET and HER2 in a subset of GC patients. MET inhibitor volitinib could significantly inhibit cell proliferation and xenograft growth in vitro and in vivo in MKN45 cells with MET and phosphorylated MET (pMET) high expressions via suppressing downstream PI3K/Akt and MAPK signaling pathways. Furthermore, combination therapy targeting both MET and HER2 demonstrated a synergistic antitumor activity.ConclusionsMET expression is altered post chemotherapy and MET status should be evaluated in real-time. Both MET and pMET expressions might need to be considered for patients suitable for volitinib treatment.

Highlights

  • Gastric cancer (GC) is the third most common cancer in China, causing more than 373,000 deaths annually [1]

  • Pre-treatment tumor samples from patients with unresectable/ recurrent GC who were enrolled between January 2008 and August 2013 were collected after obtaining patient informed consent and ethics committee approval from Peking University Cancer Hospital (PUCH)

  • Since our analysis found there was a concomitant overexpression of MET and human epidermal growth factor receptor 2 (HER2) in a subset of GC patients, the activity of volitinib combined with trastuzumab was explored in three gastric cancer patient-derived xenograft (PDX) models with HER2 and MET positive expressions

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Summary

Introduction

Gastric cancer (GC) is the third most common cancer in China, causing more than 373,000 deaths annually [1]. In patients with resectable cancer who undergo surgery, recurrence is common. For those patients with advanced cancer, chemotherapy is the main treatment. MET overexpression with or without gene amplification resulting in the activation of MET signaling, involving MAPK, PI3K/Akt, and STAT3 signalings, is the most frequent mechanism causing GC [7,8,9,10,11,12,13,14]. The aim of the present study was to evaluate the effects of chemotherapy on MET expression in gastric cancer (GC)

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