Research Papers:

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

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 and Sabine Tejpar _

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Oncotarget. 2017; 8:4277-4288. https://doi.org/10.18632/oncotarget.13834

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Albert Bosch-Vilaró1,*, Bart Jacobs1,*, Valentina Pomella1, Layka Abbasi Asbagh1, Richard Kirkland2, Joe Michel2, Sharat Singh2, Xinjun Liu2, Phillip Kim2, Gregory Weitsman3, Paul R Barber4, Borivoj Vojnovic3,4, Tony Ng3,5,6, Sabine Tejpar1

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

2Prometheus Laboratories, San Diego, CA, USA

3Richard Dimbleby Department of Cancer Research, Randall Division & Division of Cancer Studies, King’s College London, Guy’s Medical School Campus, London, UK

4Department of Oncology, Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK

5Breast Cancer Now Research Unit, King’s College London, London, UK

6UCL Cancer Institute, Paul O'Gorman Building, University College London, London, UK

*These authors contributed equally to this work

Correspondence to:

Sabine Tejpar, email: [email protected]

Keywords: colorectal cancer, cetuximab resistance, HER3, dimerization, feedback loop

Received: September 14, 2016     Accepted: November 30, 2016     Published: December 09, 2016


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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