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

Oncotarget. 2015 Jul 10;6(19):16902-11. doi: 10.18632/oncotarget.4642.

Abstract

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.

Keywords: ErbB-3; NRG-1β; colon cancer stem cells; vemurafenib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Proto-Oncogene Proteins B-raf / genetics*
  • Receptor, ErbB-3 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sulfonamides / pharmacology
  • Vemurafenib
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Indoles
  • NRG1 protein, human
  • Neuregulin-1
  • Sulfonamides
  • Vemurafenib
  • ERBB3 protein, human
  • Receptor, ErbB-3
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf