ErbB-3 activation by NRG-1β sustains growth and promotes vemurafenib resistance in BRAF-V600E colon cancer stem cells (CSCs)

• Published in: Oncotarget Vol. 6; no. 19; pp. 16902 - 16911
• Main Authors: Prasetyanti, Pramudita R, Capone, Emily, Barcaroli, Daniela, D'Agostino, Daniela, Volpe, Silvia, Benfante, Antonina, van Hooff, Sander, Iacobelli, Valentina, Rossi, Cosmo, Iacobelli, Stefano, Medema, Jan Paul, De Laurenzi, Vincenzo, Sala, Gianluca
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 10-07-2015
• Subjects: Animals; Antineoplastic Agents - pharmacology; Cell Proliferation; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Drug Resistance, Neoplasm - physiology; Flow Cytometry; Humans; Immunohistochemistry; Indoles - pharmacology; Mice; Mice, Nude; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Neuregulin-1 - metabolism; Oligonucleotide Array Sequence Analysis; Priority Research Paper; Proto-Oncogene Proteins B-raf - genetics; Receptor, ErbB-3 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Sulfonamides - pharmacology; Xenograft Model Antitumor Assays; colon cancer stem cells; vemurafenib; ErbB-3; NRG-1β
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.4642

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.