Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition.

Irene Caffa,Vito D’Agostino,Patrizio Odetti,Valter D Longo,Alessio Nencioni,Fiammetta Monacelli,Debora Soncini,Alessandro Provenzani,Michele Cea,Patrizia Damonte,Alberto Ballestrero

doi:10.18632/oncotarget.3689

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.

Highlights

Tyrosine kinase inhibitors (TKIs) are the mainstay of treatment in several types of cancer
Human Epidermal Growth Factor Receptor 2 (HER2) TKIs, such as lapatinib, are used in breast cancer with amplified HER2 [3] while Vascular Endothelial Growth Factor Receptor (VEGFR) TKIs and multitarget TKIs are commonly employed in renal cell carcinoma, hepatocellular carcinoma, thyroid cancer, gastrointestinal stromal tumors (GIST), and in previously treated colorectal cancer [4,5,6,7]
We show for the first time that TKIs that are commonly administered for treating solid tumors become potentiated in their activity by starvation

Summary

Introduction

Tyrosine kinase inhibitors (TKIs) are the mainstay of treatment in several types of cancer. In pre-clinical models, cycles of fasting were found to be per se sufficient to slow tumor growth, matching in some cases the efficacy of chemotherapy, and to synergize with chemotherapeutics and radiotherapy when applied in combination with them [9, 11, 12] Another possible advantage of administering chemotherapy during fasting is that its overall tolerability appears to be increased, potentially allowing to administer higher doses of chemotherapeutics without severe toxicity [10, 13, 14]. In the light of these results, further evaluations of the potential of these approaches, both at the preclinical and at the clinical level, are warranted [15, 16] The purpose of this preclinical study was to determine whether administering TKIs during fasting would increase their efficacy and to investigate the mechanisms underlying these effects

Results

Discussion

Methods