Priority Research Papers:
Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition
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Irene Caffa1, Vito D’Agostino2, Patrizia Damonte1, Debora Soncini1, Michele Cea1, Fiammetta Monacelli1, Patrizio Odetti1,3, Alberto Ballestrero1,3, Alessandro Provenzani2, Valter D. Longo4,5 and Alessio Nencioni1,3
1 Department of Internal Medicine, University of Genoa, Genoa, Italy
2 Laboratory of Genomic Screening, Centre for Integrative Biology, CIBIO, University of Trento, Trento, Italy
3 IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
4 Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
5 IFOM, FIRC Institute of Molecular Oncology, Milan, Italy
Valter D. Longo, email:
Alessio Nencioni, email:
Keywords: tyrosine kinase inhibitors, fasting, MAPK pathway, E2F transcription factors, cell cycle regulation
Received: March 04, 2015 Accepted: March 11, 2015 Published: March 30, 2015
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.
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