title: Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition.
abstract: Tyrosine kinase inhibitors (TKIs) are now the mainstay of treatment in many types of cancer. However, their benefit is frequently short-lived, mandating the search for safe potentiation strategies. Cycles of fasting enhance the activity of chemo-radiotherapy in preclinical cancer models and dietary approaches based on fasting are currently explored in clinical trials. Whether combining fasting with TKIs is going to be potentially beneficial remains unknown. Here we report that starvation conditions increase the ability of commonly administered TKIs, including erlotinib, gefitinib, lapatinib, crizotinib and regorafenib, to block cancer cell growth, to inhibit the mitogen-activated protein kinase (MAPK) signaling pathway and to strengthen E2F-dependent transcription inhibition. In cancer xenografts models, both TKIs and cycles of fasting slowed tumor growth, but, when combined, these interventions were significantly more effective than either type of treatment alone. In conclusion, cycles of fasting or of specifically designed fasting-mimicking diets should be evaluated in clinical studies as a means to potentiate the activity of TKIs in clinical use.
authors.affiliation: Department of Internal Medicine, University of Genoa, Genoa, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Caffa
authors.affiliation: Laboratory of Genomic Screening, Centre for Integrative Biology, CIBIO, University of Trento, Trento, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: D'Agostino
authors.affiliation: Department of Internal Medicine, University of Genoa, Genoa, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Damonte
authors.affiliation: Department of Internal Medicine, University of Genoa, Genoa, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Soncini
authors.affiliation: Department of Internal Medicine, University of Genoa, Genoa, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Cea
authors.affiliation: Department of Internal Medicine, University of Genoa, Genoa, Italy.
authors.forename: Fiammetta
authors.initials: F
authors.lastname: Monacelli
authors.affiliation: Department of Internal Medicine, University of Genoa, Genoa, Italy.|IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Patrizio
authors.initials: P
authors.lastname: Odetti
authors.affiliation: Department of Internal Medicine, University of Genoa, Genoa, Italy.|IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ballestrero
authors.affiliation: Laboratory of Genomic Screening, Centre for Integrative Biology, CIBIO, University of Trento, Trento, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Provenzani
authors.affiliation: Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA.|IFOM, FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Valter D
authors.initials: VD
authors.lastname: Longo
authors.affiliation: Department of Internal Medicine, University of Genoa, Genoa, Italy.|IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Nencioni
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005215:Fasting / Q000502:physiology*; D005260:Female; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors
keywords: E2F transcription factors; MAPK pathway; cell cycle regulation; fasting; tyrosine kinase inhibitors