MET inhibitor PHA-665752 suppresses the hepatocyte growth factor-induced cell proliferation and radioresistance in nasopharyngeal carcinoma cells

Highlights

• We demonstrated that irradiation induced MET overexpression and activation.

• The aberrant MET signal mediated by HGF induced proliferation and radioresistance of NPC cells.

• MET inhibitor PHA-665752 effectively suppressed HGF induced cell proliferation and radioresistance in NPC cells.

• PHA-665752 suppressed the three downstream pathway of HGF/MET signal in a dose-dependent manner.

Abstract

Although ionizing radiation (IR) has provided considerable improvements in nasopharyngeal carcinoma (NPC), in subsets of patients, radioresistance is still a major problem in the treatment. In this study, we demonstrated that irradiation induced MET overexpression and activation, and the aberrant MET signal mediated by hepatocyte growth factor (HGF) induced radioresistance. We also found that MET inhibitor PHA-665752 effectively suppressed HGF induced cell proliferation and radioresistance in NPC cells. Further investigation indicated that PHA-665752 suppressed the phosphorylation of the Akt, ERK1/2, and STAT3 proteins in a dose-dependent manner. Our data indicated that the combination of IR with a MET inhibitor, such as PHA-665752, might be a promising therapeutic strategy for NPC.

Introduction

Nasopharyngeal carcinoma (NPC) is the most common cancer of the head and neck, and it is highly prevalent and endemic in Southern China and Southeast Asia, with an annual incidence rate of approximately 20 cases per 100,000 people in endemic areas [1]. The epidemiological evidence implies that environmental risk factors, Epstein-Barr virus (EBV) infection and genetic susceptibility play crucial roles in the carcinogenesis of NPC [2]. Whereas radiation therapy (RT) has remained the mainstay of treatment for early stage NPC, after primary treatment with radiotherapy or chemo-irradiation, more than 30% of patients will relapse with local or regional recurrence or distant metastasis [3]. Concurrent or palliative chemotherapy is given with radiotherapy for the treatment of locally advanced disease, such as stage III and non-metastatic stage IV disease [4], [5]. The overall survival after recurrence is poor, with median survival ranging from 7.2 to 22 months [6], [7], [8]. Because of the advent of molecular targeted therapy over the past decade, some reagents such as the anti-EGFR antibody, cetuximab, and the anti-VEGF antibody, bevacizumab, have been employed against NPC [9], [10]. Increasing evidence has shown that the combination of molecular target reagents and radiation might provide a more effective therapeutic strategy for NPC. However, the influence of molecular targeted therapy to the radiosensitivity of NPC has rarely been investigated.

MET, a transmembrane receptor tyrosine kinase, consists of a 45-kD a and a 150-kD subunit [11]. HGF, the only known ligand, binds to the extracellular region, leading to receptor dimerization and phosphorylation of the intracellular tyrosine kinase domains [11]. The activation/phosphorylation of the intracellular domain prompts activation of downstream signaling, predominantly through the phosphatidylinositide 3-kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK), and signal transducers and activators of the transcription (STAT) pathways [11], [12], [13], [14]. MET has important roles in the malignant transformation of cancer cells [11]. Targeting MET has shown promise for the treatment of various types of cancer and is currently being tested in phase III trials for non-small cell lung cancer (NSCLC). In NPC, high MET expression was statistically significant for negative prognostic factors of survival [15].

Many studies have shown that MET is an attractive candidate for targeted anticancer therapy, frequently in combination with chemotherapy [16]. MET plays important roles in cancer metastasis and DNA damage and repair pathways [17], [18]. Studies have shown that MET was involved in the radioresistance of tumors such as prostate cancer and brain metastasis of breast cancer [19], [20]. Ionizing radiation induces overexpression and activity of the MET oncogene, which promotes cell invasion and protects cells from apoptosis, thus supporting radioresistance [21]. Since the radiotherapy is essential in the treatments of NPC, the role of MET inhibition to the radiosensitivity of NPC should be evaluated specifically.

In this study, we investigated the anti-tumor and radiation-sensitizing effects of MET inhibitor PHA-665752 in NPC cells. Our findings suggested that the combination of MET inhibition and radiation might lead to important clinical benefits in NPC and provide the basis for further development of a targeted therapeutic strategy for NPC.