title: Feedback activation of HER3 attenuates response to EGFR inhibitors in colon cancer cells.
abstract: 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.
authors.affiliation: Laboratory of Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Albert
authors.initials: A
authors.lastname: Bosch-Vilaró
authors.affiliation: Laboratory of Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Jacobs
authors.affiliation: Laboratory of Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Valentina
authors.initials: V
authors.lastname: Pomella
authors.affiliation: Laboratory of Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Layka
authors.initials: L
authors.lastname: Abbasi Asbagh
authors.affiliation: Prometheus Laboratories, San Diego, CA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Kirkland
authors.affiliation: Prometheus Laboratories, San Diego, CA, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Michel
authors.affiliation: Prometheus Laboratories, San Diego, CA, USA.
authors.forename: Sharat
authors.initials: S
authors.lastname: Singh
authors.affiliation: Prometheus Laboratories, San Diego, CA, USA.
authors.forename: Xinjun
authors.initials: X
authors.lastname: Liu
authors.affiliation: Prometheus Laboratories, San Diego, CA, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Kim
authors.affiliation: Richard Dimbleby Department of Cancer Research, Randall Division & Division of Cancer Studies, King's College London, Guy's Medical School Campus, London, UK.
authors.forename: Gregory
authors.initials: G
authors.lastname: Weitsman
authors.affiliation: Department of Oncology, Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Barber
authors.affiliation: Richard Dimbleby Department of Cancer Research, Randall Division & Division of Cancer Studies, King's College London, Guy's Medical School Campus, London, UK.|Department of Oncology, Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: Borivoj
authors.initials: B
authors.lastname: Vojnovic
authors.affiliation: Richard Dimbleby Department of Cancer Research, Randall Division & Division of Cancer Studies, King's College London, Guy's Medical School Campus, London, UK.|Breast Cancer Now Research Unit, King's College London, London, UK.|UCL Cancer Institute, Paul O'Gorman Building, University College London, London, UK.
authors.forename: Tony
authors.initials: T
authors.lastname: Ng
authors.affiliation: Laboratory of Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000068818:Cetuximab / Q000494:pharmacology*; D003110:Colonic Neoplasms; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D025461:Feedback, Physiological; D006801:Humans; D000077341:Lapatinib; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D055503:Protein Multimerization; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000068818:Cetuximab; D066246:ErbB Receptors; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human
keywords: HER3; cetuximab resistance; colorectal cancer; dimerization; feedback loop