Targeting Epithelial-to-Mesenchymal Transition with Met Inhibitors Reverts Chemoresistance in Small Cell Lung Cancer

• Published in: Clinical cancer research 2014-02, Vol.20 (4), p.938-950
• Main Authors: CANADAS, Israel, ROJO, Federico, MOJAL, Sergi, DE HERREROS, Antonio García, ROVIRA, Ana, ALBANELL, Joan, ARRIOLA, Edurne, TAUS, Alvaro, ARPI, Oriol, ARUMI-URIA, Montserrat, PIJUAN, Lara, MENENDEZ, Silvia, ZAZO, Sandra, DOMINE, Manuel, SALIDO, Marta
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Carcinogenesis; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Epithelial-Mesenchymal Transition - drug effects; Etoposide - pharmacology; Etoposide - therapeutic use; Gene Expression; Hepatocyte Growth Factor - physiology; Humans; Kaplan-Meier Estimate; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Pharmacology. Drug treatments; Piperidines - pharmacology; Piperidines - therapeutic use; Pneumology; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Proto-Oncogene Proteins c-met - metabolism; Pyrazoles; Pyridines - pharmacology; Pyridines - therapeutic use; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - enzymology; Small Cell Lung Carcinoma - mortality; Small Cell Lung Carcinoma - pathology; Snail Family Transcription Factors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumors; Tumors of the respiratory system and mediastinum; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-13-1330

Met receptor phosphorylation is associated with poor prognosis in human small cell lung cancer (SCLC). The aim of our work was to investigate the effects of hepatocyte growth factor (HGF)/Met-mediated epithelial-to-mesenchymal transition (EMT) in SCLC and to evaluate the role of Met inhibition in mesenchymal/chemorefractory SCLC models. SCLC models of HGF-induced EMT were evaluated in vitro and in vivo (subcutaneous xenografts in BALB/c nude mice) for chemosensitivity and response to Met inhibition with PF-2341066 (crizotinib). Human SCLC samples at diagnosis (N = 87) and relapse (N = 5) were evaluated by immunohistochemistry and immunofluorescence for EMT markers and Met status and these were correlated with patient outcome. We identified that the activation of the Met receptor through HGF induced expression of mesenchymal markers, an aggressive phenotype, and chemoresistance. Blockade of this process with the Met inhibitor resensitized cells to chemotherapy in vitro and in vivo. Moreover, mesenchymal markers in human SCLC specimens were associated with Met activation, predicted worse survival, and were upregulated in chemorefractory disease. These results provide novel evidence on an important role of Met-dependent EMT in the adverse clinical behavior of SCLC and support clinical trials of Met inhibitors and chemotherapy in this fatal disease.