title: ErbB2 signaling activates the Hedgehog pathway via PI3K-Akt in human esophageal adenocarcinoma: identification of novel targets for concerted therapy concepts.
abstract: The Hedgehog pathway plays an important role in the pathogenesis of several tumor types, including esophageal cancer. In our study, we show an expression of the ligand Indian hedgehog (Ihh) and its downstream mediator Gli-1 in primary resected adenocarcinoma tissue by immunohistochemistry and quantitative PCR in fifty percent of the cases, while matching healthy esophagus mucosa was negative for both proteins. Moreover, a functionally important regulation of Gli-1 by ErbB2-PI3K-mTORC signaling as well as a Gli-1-dependent regulation of Ihh in the ErbB2 amplified esophageal adenocarcinoma cell line OE19 was observed. Treatment of OE19 cells with the Her2 antibody trastuzumab, the PI3K-mTORC1 inhibitor NVP BEZ235 (BEZ235) or the knockdown of Akt1 resulted in a downregulation of Gli-1 and Ihh as well as in a reduction of viable OE19 cells in vitro. Interestingly, the Hedgehog receptor Smo, which acts upstream of Gli-1, was not expressed in OE19 cells and in the majority of primary human esophageal adenocarcinoma, suggesting a non-canonical upregulation of Gli-1 expression by the ErbB2-PI3K axis. To translate our findings into a therapeutic concept, we targeted ErbB2-PI3K-mTORC1 by trastuzumab and BEZ235, combining both compounds with the Gli-1/2 inhibitor GANT61. The triple combination led to significantly stronger reduction of tumor cell viability than cisplatinum or each biological alone. Therefore, concomitant blockage of the ErbB2-PI3K pathway and the Hedgehog downstream mediator Gli-1 may provide a new therapeutic strategy for esophageal cancer.
authors.affiliation: Hubertus Wald Tumorzentrum, Department of Oncology-Hematology, Bone Marrow Transplantation and Pneumology, University Cancer Center, Hamburg, Germany.
authors.forename: Maxim
authors.initials: M
authors.lastname: Kebenko
authors.affiliation: Department of General, Visceral and Thoracic Surgery, Hamburg, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Drenckhan
authors.affiliation: Department of General, Visceral and Thoracic Surgery, Hamburg, Germany.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Gros
authors.affiliation: Institute of Biochemistry and Signal Transduction, University Medical Center Eppendorf, Hamburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Jücker
authors.affiliation: Institute of Biochemistry and Signal Transduction, University Medical Center Eppendorf, Hamburg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Grabinski
authors.affiliation: Institute of Biochemistry and Signal Transduction, University Medical Center Eppendorf, Hamburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Ewald
authors.affiliation: Institute of Biochemistry and Signal Transduction, University Medical Center Eppendorf, Hamburg, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Grottke
authors.affiliation: Hubertus Wald Tumorzentrum, Department of Oncology-Hematology, Bone Marrow Transplantation and Pneumology, University Cancer Center, Hamburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schultze
authors.affiliation: Department of General, Visceral and Thoracic Surgery, Hamburg, Germany.
authors.forename: Jakob R
authors.initials: JR
authors.lastname: Izbicki
authors.affiliation: Hubertus Wald Tumorzentrum, Department of Oncology-Hematology, Bone Marrow Transplantation and Pneumology, University Cancer Center, Hamburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.affiliation: Hubertus Wald Tumorzentrum, Department of Oncology-Hematology, Bone Marrow Transplantation and Pneumology, University Cancer Center, Hamburg, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Wellbrock
authors.affiliation: Hubertus Wald Tumorzentrum, Department of Oncology-Hematology, Bone Marrow Transplantation and Pneumology, University Cancer Center, Hamburg, Germany. Electronic address: fiedler@uke.de.
authors.forename: Walter
authors.initials: W
authors.lastname: Fiedler
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004947:Esophagus / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured; D000071676:Zinc Finger Protein GLI1
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D007093:Imidazoles; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D011743:Pyrimidines; D011804:Quinolines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D000068878:Trastuzumab; D000071676:Zinc Finger Protein GLI1; C551027:GANT 61; C400551:GLI1 protein, human; C508053:ERBB2 protein, human; C531198:dactolisib
keywords: ErbB2–Akt; Esophageal cancer; Gli; Hedgehog; Non-canonical