Combined MET Inhibition and Topoisomerase I Inhibition Block Cell Growth of Small Cell Lung Cancer

Abstract

Small cell lung cancer (SCLC) is a devastating disease, and current therapies have not greatly improved the 5-year survival rates. Topoisomerase (Top) inhibition is a treatment modality for SCLC; however, the response is short lived. Consequently, our research has focused on improving SCLC therapeutics through the identification of novel targets. Previously, we identified MNNG HOS transforming gene (MET) to be overexpressed and functional in SCLC. Herein, we investigated the therapeutic potential of combinatorial targeting of MET using SU11274 and Top1 using 7-ethyl-10-hydroxycamptothecin (SN-38). MET and TOP1 gene copy numbers and protein expression were determined in 29 patients with limited (n = 11) and extensive (n = 18) disease. MET gene copy number was significantly increased (>6 copies) in extensive disease compared with limited disease (P = 0.015). Similar TOP1 gene copy numbers were detected in limited and extensive disease. Immunohistochemical staining revealed a significantly higher Top1 nuclear expression in extensive (0.93) versus limited (0.15) disease (P = 0.04). Interestingly, a significant positive correlation was detected between MET gene copy number and Top1 nuclear expression (r = 0.5). In vitro stimulation of H82 cells revealed hepatocyte growth factor (HGF)–induced nuclear colocalization of p-MET and Top1. Furthermore, activation of the HGF/MET axis enhanced Top1 activity, which was abrogated by SU11274. Combination of SN-38 with SU11274 dramatically decreased SCLC growth as compared with either drug alone. Collectively, these findings suggest that the combinatorial inhibition of MET and Top1 is a potentially efficacious treatment strategy for SCLC.

The anti-apoptotic BAG3 protein is expressed in lung carcinomas and regulates small cell lung carcinoma (SCLC) tumor growth

“…The molecular mechanisms and the proteins involved in BAG3 pro-survival function in SCLCs are still unknown and require further studies. Recent reports indicate a relevant role for the MET signaling pathway in SCLC biology [ 12 , 13 , 14 , 15 ]. Indeed, Met receptor phosphorylation induced by HGF is associated to the hyperexpression of mesenchymal markers and chemoresistance that result in a poor prognosis in SCLC patients [ 14 , 15 ].…”

“…Recent reports indicate a relevant role for the MET signaling pathway in SCLC biology [ 12 , 13 , 14 , 15 ]. Indeed, Met receptor phosphorylation induced by HGF is associated to the hyperexpression of mesenchymal markers and chemoresistance that result in a poor prognosis in SCLC patients [ 14 , 15 ]. Furthermore, MET receptor signaling leads to the activation of PI3K–Akt signaling, Ras–MAP kinase cascade, STAT3 and NF-κB activation, promoting cell survival, proliferation and invasiveness [ 16 ].…”

Human papillomavirus oncoprotein E6 upregulates c-Met through p53 downregulation

“…For inhibitor treatment, 2×10 3 cells were plated in 96-well plates and allowed to grow overnight, then cells were exposed to different concentrations of SU11274 (0, 0.05, 0.25, 1.25, 6.25 and 31.25 µM) and allowed to grow for 1, 2, and 3 days, respectively, before harvesting for colorimetric measurements. The dose selection was based on previous studies (26, 27). All the experiments were performed in triplicate.…”

MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale

“…MET inhibition is also synergistic with cisplatin in SCCHN cancer cell lines (25) and also appears to be synergistic with radiation in cell lines in some studies, although crizotinib (Pfizer), an inhibitor of MET, anaplastic lymphoma kinase (ALK), and ROS1 kinases, failed to enhance the effects of radiation in SCCHN xenograft models (27). Furthermore, MET inhibition was synergistic with topoisomerase-I inhibition in SCLC cell lines, with a significant positive correlation observed between MET gene copy number (GCN) and topoisomerase-I nuclear expression (28).…”