title: Activation of HER3 interferes with antitumor effects of Axl receptor tyrosine kinase inhibitors: suggestion of combination therapy.
abstract: The Axl receptor tyrosine kinase (RTK) has been established as a strong candidate for targeted therapy of cancer. However, the benefits of targeted therapies are limited due to acquired resistance and activation of alternative RTKs. Therefore, we asked if cancer cells are able to overcome targeted Axl therapies. Here, we demonstrate that inhibition of Axl by short interfering RNA or the tyrosine kinase inhibitor (TKI) BMS777607 induces the expression of human epidermal growth factor receptor 3 (HER3) and the neuregulin 1(NRG1)-dependent phosphorylation of HER3 in MDA-MB231 and Ovcar8 cells. Moreover, analysis of 20 Axl-expressing cancer cell lines of different tissue origin indicates a low basal phosphorylation of RAC-α serine/threonine-protein kinase (AKT) as a general requirement for HER3 activation on Axl inhibition. Consequently, phosphorylation of AKT arises as an independent biomarker for Axl treatment. Additionally, we introduce phosphorylation of HER3 as an independent pharmacodynamic biomarker for monitoring of anti-Axl therapy response. Inhibition of cell viability by BMS777607 could be rescued by NRG1-dependent activation of HER3, suggesting an escape mechanism by tumor microenvironment. The Axl-TKI MPCD84111 simultaneously blocked Axl and HER2/3 signaling and thereby prohibited HER3 feedback activation. Furthermore, dual inhibition of Axl and HER2/3 using BMS777607 and lapatinib led to a significant inhibition of cell viability in Axl-expressing MDA-MB231 and Ovcar8 cells. Therefore, we conclude that, in patient cohorts with expression of Axl and low basal activity of AKT, a combined inhibition of Axl and HER2/3 kinase would be beneficial to overcome acquired resistance to Axl-targeted therapies.
authors.affiliation: Department of Molecular Biology, Max Planck Institute of Biochemistry, Martinsried, Germany. Electronic address: torka@biochem.mpg.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Torka
authors.affiliation: Department of Molecular Biology, Max Planck Institute of Biochemistry, Martinsried, Germany; MTA-SE (Magyar Tudományos Akadémia -Semmelweis Egyetem) Pathobiochemistry Research Group, Department of Medical Chemistry, Semmelweis University, Budapest, Hungary.
authors.forename: Kinga
authors.initials: K
authors.lastname: Pénzes
authors.affiliation: Department of Molecular Biology, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Gusenbauer
authors.affiliation: Department of Molecular Biology, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Baumann
authors.affiliation: Vichem Chemie Research Ltd, Budapest, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Szabadkai
authors.affiliation: Vichem Chemie Research Ltd, Budapest, Hungary; Department of Pharmaceutical Chemistry, Semmelweis University, Budapest, Hungary.
authors.forename: Lászlȯ
authors.initials: L
authors.lastname: Őrfi
authors.affiliation: Vichem Chemie Research Ltd, Budapest, Hungary; MTA-SE (Magyar Tudományos Akadémia -Semmelweis Egyetem) Pathobiochemistry Research Group, Department of Medical Chemistry, Semmelweis University, Budapest, Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Kéri
authors.affiliation: Department of Molecular Biology, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D000077341:Lapatinib; D008024:Ligands; D051379:Mice; D009185:Myelin Proteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000070816:Nogo Receptor 1; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D055503:Protein Multimerization / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D020893:Receptor, ErbB-3 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000970:Antineoplastic Agents; D058851:GPI-Linked Proteins; D000077341:Lapatinib; D008024:Ligands; D009185:Myelin Proteins; D000070816:Nogo Receptor 1; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011956:Receptors, Cell Surface; D000094963:Axl Receptor Tyrosine Kinase; C486580:RTN4R protein, human