Impact of MET inhibition on small‐cell lung cancer cells showing aberrant activation of the hepatocyte growth factor/MET pathway

Abstract

Small‐cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers, and is characterized as extremely aggressive, often displaying rapid tumor growth and multiple organ metastases. In addition, the clinical outcome of SCLC patients is poor due to early relapse and acquired resistance to standard chemotherapy treatments. Hence, novel therapeutic strategies for the treatment of SCLC are urgently required. Accordingly, several molecular targeted therapies were evaluated in SCLC; however, they failed to improve the clinical outcome. The receptor tyrosine kinase MET is a receptor for hepatocyte growth factor (HGF), and aberrant activation of HGF/MET signaling is known as one of the crucial mechanisms enabling cancer progression and invasion. Here, we found that the HGF/MET signaling was aberrantly activated in chemoresistant or chemorelapsed SCLC cell lines (SBC‐5, DMS273, and DMS273‐G3H) by the secretion of HGF and/or MET copy number gain. A cell‐based in vitro assay revealed that HGF/MET inhibition, induced either by MET inhibitors (crizotinib and golvatinib), or by siRNA‐mediated knockdown of HGF or MET, constrained growth of chemoresistant SCLC cells through the inhibition of ERK and AKT signals. Furthermore, treatment with either crizotinib or golvatinib suppressed the systemic metastasis of SBC‐5 cell tumors in natural killer cell‐depleted SCID mice, predominantly through cell cycle arrest. These findings reveal the therapeutic potential of targeting the HGF/MET pathway for inhibition, to constrain tumor progression of SCLC cells showing aberrant activation of HGF/MET signaling. We suggest that it would be clinically valuable to further investigate HGF/MET‐mediated signaling in SCLC cells.

Osimertinib Overcomes Alectinib Resistance Caused by Amphiregulin in a Leptomeningeal Carcinomatosis Model of ALK-Rearranged Lung Cancer

“…To establish the LMC model, mouse scalps were sterilized with 70% ethanol, and tumor cells (2 Â 10 5 ) were injected into the leptomeningeal space (between the external occipital protuberance and first cervical vertebra) with a 27-gauge needle. 20 In the LMC model, tumor quantity was tracked in live mice by repeated noninvasive optical imaging of tumor-specific luciferase activity using the IVIS Lumina XR Imaging System (PerkinElmer, Alameda, CA), as previously described. 19,20 This study was performed in strict accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals by the Ministry of Education, Culture, Sports, Science and Technology in Japan.…”

“…20 In the LMC model, tumor quantity was tracked in live mice by repeated noninvasive optical imaging of tumor-specific luciferase activity using the IVIS Lumina XR Imaging System (PerkinElmer, Alameda, CA), as previously described. 19,20 This study was performed in strict accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals by the Ministry of Education, Culture, Sports, Science and Technology in Japan. The protocol was approved by the Committee on the Ethics of Experimental Animals and the Advanced Science Research Center, Kanazawa University, Kanazawa, Japan (approval no.…”

High Expression of NEK2 and PIM1, but Not PIM3, Is Linked to an Aggressive Phenotype of Bronchopulmonary Neuroendocrine Neoplasms

“…PIM1, in turn, was shown to enhance the growth of lung adenocarcinoma by potentiating the c-MET signaling pathway [ 41 ] and the growth of prostate carcinoma [ 48 ] and triple-negative breast cancer [ 49 ] in cooperation with MYC. Importantly, some reports suggest the involvement of AKT, Wnt, MYC, and MET also in SCLC pathogenesis [ 50 – 53 ]. Hence, further studies are needed to elucidate whether overexpressed NEK2 and PIM1 induce similar promoting effects in SCLC.…”

MET Inhibitors in Small Cell Lung Cancer: From the Bench to the Bedside

“…In this case, combination with chemotherapy was not assessed. In a more recent work, Taniguchi et al [87] also showed similar results, both in vitro and in vivo, with E7050 (golvatinib), a dual kinase inhibitor of MET and vascular endothelial growth factor receptor-2 (VEGFR-2), which is currently under clinical development [88]. Growth of SCLC cell lines expressing HGF and phosphorylated-MET (confirmed using Western blot and Enzyme-linked immunosorbent assay) was constrained after in vitro treatment with golvatinib.…”