Oncotarget

Research Papers:

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

Claudia Fumarola _, Daniele Cretella, Silvia La Monica, Mara A. Bonelli, Roberta Alfieri, Cristina Caffarra, Federico Quaini, Denise Madeddu, Angela Falco, Andrea Cavazzoni, Graziana Digiacomo, Giulia Mazzaschi, Valentina Vivo, Elisabetta Barocelli, Marcello Tiseo, Pier Giorgio Petronini and Andrea Ardizzoni

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Oncotarget. 2017; 8:91841-91859. https://doi.org/10.18632/oncotarget.19279

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Abstract

Claudia Fumarola1, Daniele Cretella1, Silvia La Monica1, Mara A. Bonelli1, Roberta Alfieri1, Cristina Caffarra1, Federico Quaini1, Denise Madeddu1, Angela Falco1, Andrea Cavazzoni1, Graziana Digiacomo1, Giulia Mazzaschi1, Valentina Vivo2, Elisabetta Barocelli2, Marcello Tiseo3, Pier Giorgio Petronini1,* and Andrea Ardizzoni4,*

1Department of Medicine and Surgery, University of Parma, Parma, Italy

2Food and Drug Department, University of Parma, Parma, Italy

3Medical Oncology Unit, University Hospital of Parma, Parma, Italy

4Division of Medical Oncology, Sant’Orsola-Malpighi University Hospital, Bologna, Italy

*Joint last authors

Correspondence to:

Claudia Fumarola, email: [email protected]

Mara A. Bonelli, email: [email protected]

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.


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