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BDNF/TrkB signaling protects HT-29 human colon cancer cells from EGFR inhibition

Caroline Brunetto de Farias1, Tiago Elias Heinen, Rafael Pereira dos Santos

  • 1Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS, Brazil.

Biochemical and Biophysical Research Communications
|July 31, 2012
PubMed

Insights

Brain-derived neurotrophic factor (BDNF) signaling may drive resistance to anti-epidermal growth factor receptor (EGFR) therapies in colorectal cancer (CRC). Targeting TrkB could enhance the effectiveness of EGFR blockade in CRC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Clinical success of targeted colorectal cancer (CRC) treatments is often hindered by resistance to anti-epidermal growth factor receptor (EGFR) therapy.
  • Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are emerging as potential anticancer targets, with elevated BDNF levels previously observed in CRC tumors.

Purpose of the Study:

  • To investigate the role of BDNF/TrkB signaling in mediating resistance to anti-EGFR therapy in colorectal cancer.
  • To explore the potential of targeting TrkB to overcome resistance and enhance anti-EGFR treatment efficacy.

Main Methods:

  • In vitro experiments using human HT-29 CRC cells.
  • Treatment with anti-EGFR monoclonal antibody cetuximab.
  • Assessment of cell proliferation, survival, and mRNA expression of BDNF and TrkB.
  • Administration of human recombinant BDNF and Trk inhibitor K252a.

Main Results:

  • Cetuximab treatment reduced proliferation and BDNF/TrkB mRNA expression in HT-29 cells.
  • Recombinant BDNF counteracted the inhibitory effects of cetuximab on cell proliferation and survival.
  • The Trk inhibitor K252a synergistically enhanced cetuximab's effect on cell proliferation, an effect blocked by BDNF.

Conclusions:

  • Increased BDNF/TrkB signaling is implicated as a mechanism of resistance to EGFR blockade in colorectal cancer.
  • Targeting TrkB presents a potential strategy to potentiate the anticancer effects of anti-EGFR therapies in CRC.

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