Priority Research Papers:
ErbB-3 activation by NRG-1β sustains growth and promotes vemurafenib resistance in BRAF-V600E colon cancer stem cells (CSCs)
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Pramudita R. Prasetyanti1,2, Emily Capone3, Daniela Barcaroli3, Daniela D’Agostino3, Silvia Volpe3, Antonina Benfante4, Sander van Hooff1,2, Valentina Iacobelli5, Cosmo Rossi3, Stefano Iacobelli3,6, Jan Paul Medema1,2, Vincenzo De Laurenzi3 and Gianluca Sala3,6
1 Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, Academic Medical Center (AMC), Amsterdam, The Netherlands
2 Cancer Genomics Center, The Netherlands
3 Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University “G. d’Annunzio” Chieti-Pescara, Centro Studi sull’Invecchiamento, Ce.S.I., Chieti, Italy
4 Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy
5 Department of Gynecology and Obstetrics, La Sapienza University of Rome, Rome, Italy
6 MediaPharma s.r.l., Chieti, Italy
Gianluca Sala, email:
Keywords: ErbB-3, vemurafenib, NRG-1β, colon cancer stem cells
Received: May 06, 2015 Accepted: June 12, 2015 Published: June 25, 2015
Approximately 5-10% of metastatic colorectal cancers harbor a BRAF-V600E mutation, which is correlated with resistance to EGFR-targeted therapies and worse clinical outcome. Vice versa, targeted inhibition of BRAF-V600E with the selective inhibitor PLX 4032 (Vemurafenib) is severely limited due to feedback re-activation of EGFR in these tumors. Mounting evidence indicates that upregulation of the ErbB-3 signaling axis may occur in response to several targeted therapeutics, including Vemurafenib, and NRG-1β-dependent re-activation of the PI3K/AKT survival pathway has been associated with therapy resistance.
Here we show that colon CSCs express, next to EGFR and ErbB-2, also significant amounts of ErbB-3 on their membrane. This expression is functional as NRG-1β strongly induces AKT/PKB and ERK phosphorylation, cell proliferation, clonogenic growth and promotes resistance to Vemurafenib in BRAF-V600E mutant colon CSCs. This resistance was completely dependent on ErbB-3 expression, as evidenced by knockdown of ErbB-3. More importantly, resistance could be alleviated with therapeutic antibody blocking ErbB-3 activation, which impaired NRG-1β-driven AKT/PKB and ERK activation, clonogenic growth in vitro and tumor growth in xenograft models. In conclusion, our findings suggest that targeting ErbB-3 receptors could represent an effective therapeutic approach in BRAF-V600E mutant colon cancer.
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