Enhancement of the anti-tumor activity of FGFR1 inhibition in squamous cell lung cancer by targeting downstream signaling involved in glucose metabolism

Autor: Marcello Tiseo, Elisabetta Barocelli, Federico Quaini, Giulia Mazzaschi, Roberta Alfieri, Andrea Cavazzoni, Mara A. Bonelli, Daniele Cretella, Claudia Fumarola, Pier Giorgio Petronini, Angela Falco, Silvia La Monica, Graziana Digiacomo, Cristina Caffarra, Andrea Ardizzoni, Denise Madeddu, Valentina Vivo
Přispěvatelé: Fumarola, Claudia, Cretella, Daniele, La Monica, Silvia, Bonelli, Mara A., Alfieri, Roberta, Caffarra, Cristina, Quaini, Federico, Madeddu, Denise, Falco, Angela, Cavazzoni, Andrea, Digiacomo, Graziana, Mazzaschi, Giulia, Vivo, Valentina, Barocelli, Elisabetta, Tiseo, Marcello, Petronini, Pier Giorgio, Ardizzoni, Andrea
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Zdroj: Oncotarget
Popis: // Claudia Fumarola 1 , Daniele Cretella 1 , Silvia La Monica 1 , Mara A. Bonelli 1 , Roberta Alfieri 1 , Cristina Caffarra 1 , Federico Quaini 1 , Denise Madeddu 1 , Angela Falco 1 , Andrea Cavazzoni 1 , Graziana Digiacomo 1 , Giulia Mazzaschi 1 , Valentina Vivo 2 , Elisabetta Barocelli 2 , Marcello Tiseo 3 , Pier Giorgio Petronini 1, * and Andrea Ardizzoni 4, * 1 Department of Medicine and Surgery, University of Parma, Parma, Italy 2 Food and Drug Department, University of Parma, Parma, Italy 3 Medical Oncology Unit, University Hospital of Parma, Parma, Italy 4 Division of Medical Oncology, Sant’Orsola-Malpighi University Hospital, Bologna, Italy * Joint last authors Correspondence to: Claudia Fumarola, email: claudia.fumarola@unipr.it Mara A. Bonelli, email: mara.bonelli@unipr.it Keywords: FGFR1, glucose metabolism, dovitinib, NVP-BGJ398, SQCLC Received: March 03, 2017 Accepted: June 18, 2017 Published: July 17, 2017 ABSTRACT Fibroblast Growth Factor Receptor (FGFR) signaling is a complex pathway which controls several processes, including cell proliferation, survival, migration, and metabolism. FGFR1 signaling is frequently deregulated via amplification/over-expression in NSCLC of squamous histotype (SQCLC), however its inhibition has not been successfully translated in clinical setting. We determined whether targeting downstream signaling implicated in FGFR1 effects on glucose metabolism potentiates the anti-tumor activity of FGFR1 inhibition in SQCLC. In FGFR1 amplified/over-expressing SQCLC cell lines, FGF2-mediated stimulation of FGFR1 under serum-deprivation activated both MAPK and AKT/mTOR pathways and increased glucose uptake, glycolysis, and lactate production, through AKT/mTOR-dependent HIF-1α accumulation and up-regulation of GLUT-1 glucose transporter. These effects were hindered by PD173074 and NVP-BGJ398, selective FGFR inhibitors, as well as by dovitinib, a multi-kinase inhibitor. Glucose metabolism was hampered by the FGFR inhibitors also under hypoxic conditions, with consequent inhibition of cell proliferation and viability. In presence of serum, glucose metabolism was impaired only in cell models in which FGFR1 inhibition was associated with AKT/mTOR down-regulation. When the activation of the AKT/mTOR pathway persisted despite FGFR1 down-regulation, the efficacy of NVP-BGJ398 could be significantly improved by the combination with NVP-BEZ235 or other inhibitors of this signaling cascade, both in vitro and in xenotransplanted nude mice. Collectively our results indicate that inhibition of FGFR1 signaling impacts on cancer cell growth also by affecting glucose energy metabolism. In addition, this study strongly suggests that the therapeutic efficacy of FGFR1 targeting molecules in SQCLC may be implemented by combined treatments tackling on glucose metabolism.
Databáze: OpenAIRE
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