Feedback activation of HER3 attenuates response to EGFR inhibitors in colon cancer cells

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Albert Bosch-Vilaró1, Bart Jacobs1, Valentina Pomella1

  • 1Laboratory of Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.

Oncotarget
|December 30, 2016
PubMed

Insights

Cetuximab resistance in colorectal cancer involves feedback activation of HER3, partly via AKT inhibition. Combining cetuximab with lapatinib may overcome this resistance by targeting HER2:HER3 dimerization.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Cetuximab, an EGFR inhibitor, treats colorectal cancer but faces resistance.
  • Resistance mechanisms, including feedback loops, limit cetuximab efficacy.
  • The role of feedback loops in cetuximab resistance is not well understood.

Purpose of the Study:

  • Investigate feedback mechanisms driving cetuximab resistance in colorectal cancer.
  • Explore the role of HER3 and HER2 in cetuximab-induced resistance.
  • Evaluate combination therapies for overcoming cetuximab resistance.

Main Methods:

  • Utilized colon cancer cell lines.
  • Analyzed HER3 and HER2 expression and phosphorylation.
  • Assessed HER2:HER3 dimerization.
  • Performed HER3 knockdown and drug sensitivity assays.

Main Results:

  • Cetuximab treatment induced feedback upregulation and phosphorylation of HER3.
  • AKT inhibition partially mediated this HER3 upregulation.
  • Increased HER2:HER3 dimerization was observed post-cetuximab.
  • Lapatinib blocked cetuximab-induced HER3 phosphorylation.
  • Combination of cetuximab and lapatinib reduced cell viability after HER3 knockdown.

Conclusions:

  • Cetuximab treatment triggers feedback HER3 activation, potentially reducing efficacy.
  • This HER3 activation may contribute to cetuximab resistance in colorectal cancer.
  • Targeting HER3 and HER2 concurrently with cetuximab and lapatinib shows promise against resistance.
Keywords:
HER3cetuximab resistancecolorectal cancerdimerizationfeedback loop

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