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

نویسندگان

  • Albert Bosch-Vilaró
  • Bart Jacobs
  • Valentina Pomella
  • Layka Abbasi Asbagh
  • Richard Kirkland
  • Joe Michel
  • Sharat Singh
  • Xinjun Liu
  • Phillip Kim
  • Gregory Weitsman
  • Paul R. Barber
  • Borivoj Vojnovic
  • Tony Ng
  • Sabine Tejpar
چکیده

The EGFR inhibitor cetuximab is approved for the treatment of colorectal cancer. However, both innate and acquired resistance mechanisms, including compensatory feedback loops, limit its efficacy. Nevertheless, the emergence of these feedback loops has remained largely unexplored to date. Here, we showed feedback upregulation of HER3 and induction of HER3 phosphorylation after cetuximab treatment in colon cancer cells. We also showed that this upregulation occurs, at least partly, through AKT inhibition. Together with this, we observed increased HER2:HER3 dimerization upon cetuximab treatment. Interestingly, lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, blocked the increase of cetuximab-induced HER3 phosphorylation. Additionally, we showed that upon HER3 knockdown, cetuximab combined with lapatinib was able to decrease cell viability compared to HER3 expressing cells. These results suggest the existence of a cetuximab-induced feedback HER3 activation that could potentially result in reduced cetuximab efficacy in colorectal cancer patients. Taken together, we provide evidence of the limited effectiveness of cetuximab monotherapy compared to rational combinations.

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عنوان ژورنال:

دوره 8  شماره 

صفحات  -

تاریخ انتشار 2017