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Canertinib-Induced Leukemia Cell Death Signaling – Effects of a Pan Linköping University Medical Dissertations No. 1289 Canertinib-induced leukemia cell death signaling – effects of a pan-ERBB inhibitor Cecilia Trinks Division of Cell Biology Department of Clinical and Experimental Medicine Faculty of Health Sciences, SE-581 85 Linköping, Sweden Linköping 2012 © Cecilia Trinks, 2012 ISSN 0345-0082 ISBN 978-91-7519-983-2 Cover picture: Chamilly Evaldsson Illustrations made by the author, unless otherwise specified. Published articles have been reprinted with the permission of the copyright holder. Printed by LiU-Tryck Linköping, Sweden, 2012 To myself! I livets lopp finns det inget målsnöre. De snören vi passerar är starten till ett nytt lopp. SUPERVISOR Thomas Walz, MD, Associate Professor Division of Clinical Sciences Faculty of Health Sciences Linköping University, Linköping CO-SUPERVISORS Jan-Ingvar Jönsson, Professor Experimental Hematology Unit Faculty of Health Sciences Linköping University, Linköping Anna-Lotta Hallbeck, MD PhD Division of Clinical Sciences Faculty of Health Sciences Linköping University, Linköping OPPONENT Dan Grandér, Professor Department of Oncology and Pathology Cancer Center Karolinska Karolinska Institute, Stockholm ABSTRACT ABSTRACT Acute myelogenous leukemia (AML) is the most common acute leukemia affecting adults, the second most frequent leukemia in children, and remains one of the most difficult to cure. Despite a substantial progress in understanding the pathogenesis of AML, general and rather unspecific cytostatic drugs such as cytarabine and anthracyclins still make up the cornerstones of therapy. Problems with these protocols include toxicity and the occurrence of resistance to the drugs in many patients. In order to extend the treatment options and ultimately improve survival for patients with leukemia it is imperative to increase the therapeutic arsenal with effective targeted therapies, preferentially with different mechanisms of action. AML due to a substantial heterogeneity between patients and within the clones in the same patient, as well as T-cell malignancies, are particularly difficult to treat since it is almost impossible to eradicate all leukemic stem cells using chemotherapy, thus there is a need to find more specific and effective treatments. Canertinib is a novel tyrosine kinase inhibitor developed for the treatment of certain solid cancers and has been designed to specifically inhibit all member of the ERBB-receptor family (ERBB1, ERBB2, ERBB3 and ERBB4). However, there are indications that canertinib has a broader specificity and it has not been tested on patients with leukemia. The aim of this thesis was to investigate the anti-proliferative and pro-apoptotic effects and mechanisms of canertinib in human leukemia cells, and more specifically to clarify the cell death pathway and potential targets for the drug in these cells. Canertinib treatment of leukemia cell lines resulted in an ERBB-independent induction of the intrinsic apoptotic pathway and activation of caspase-10, -9, and -8 as a consequence of Akt and Erk inhibition. In the human T-cell leukemia cell line Jurkat, the effects were associated to dephosphorylation of the lymphocyte-specific proteins, Lck and Zap-70. However, as full-length ERBB receptors were absent in leukemic cell lines other possible targets for canertinib were investigated. The FLT3 receptor, frequently mutated in AML, was discovered as a target since canertinib inhibited FLT3 autophosphorylation and kinase activity as well as downstream targets. The search for other possible proteins that might account for the effect exerted by canertinib, lead to the discovery of a truncated form of ERBB2 in human leukemic cells. In conclusion, canertinib display promising anti-tumor effects on malignant hematopoietic cells and might be used in future studies in combination with conventional chemotherapy or other targeted therapies in the treatment of leukemia. TABLE OF CONTENTS TABLE OF CONTENTS LIST OF PAPERS ............................................................................................ 9 PAPERS OUTSIDE THIS THESIS .................................................................. 10 ABBREVIATIONS ........................................................................................ 11 INTRODUCTION ......................................................................................... 13 CANCER ........................................................................................................ 13 Genetic alterations ....................................................................................... 13 Oncogenes and tumor suppressor genes ..................................................... 14 Cell cycle ...................................................................................................... 14 Apoptosis ..................................................................................................... 16 Leukemia ...................................................................................................... 19 RECEPTOR TYROSINE KINASES ..................................................................... 20 Receptor tyrosine kinases in cancer ............................................................. 20 The ERBB receptor family and its ligands ............................................. 20 The ERBB2 receptor ..................................................................................... 22 The ERBB2 receptor in hematopoietic cells .................................................. 24 The FLT3 receptor ..................................................................................... 24 Intracellular signaling proteins ............................................................... 25 The PI3-K / Akt / FoxO pathway ................................................................. 25 The Ras / MAPK pathway ........................................................................... 26 Non-receptor tyrosine kinases ...................................................................... 26 CANCER THERAPY ......................................................................................... 28 Chemotherapy .............................................................................................. 28 Targeted therapy .......................................................................................... 28 Small molecule inhibitors ........................................................................ 29 FLT3 targeted therapy ................................................................................. 30 ERBB targeted therapy ................................................................................ 31 TABLE OF CONTENTS Strategies to apply kinase targeted therapy ................................................. 32 Resistance .................................................................................................... 33 Canertinib .................................................................................................... 35 AIMS OF THE THESIS ................................................................................. 37 MATERIALS AND METHODS .................................................................... 39 CELL LINES .................................................................................................... 39 PATIENT SAMPLES ......................................................................................... 39 WESTERN BLOT ANALYSIS ............................................................................. 40 FLOW CYTOMETRY ........................................................................................ 41 REVERSE-TRANSCRIBED POLYMERASE CHAIN REACTION, RT-PCR ............ 43 RESULTS AND DISCUSSION ...................................................................... 45 CONCLUSIONS ........................................................................................... 57 FUTURE ASPECTS ....................................................................................... 59 POPULÄRVETENSKAPLIG SAMMANFATTNING ....................................... 61 ACKNOWLEDGEMENTS ............................................................................. 64 REFERENCES ............................................................................................... 66 LIST OF PAPERS LIST OF PAPERS This thesis is based on the following papers, which will be referred to in the text by their Roman numerals (I-IV): I. Cecilia Trinks, Emelie A. Djerf, Anna-Lotta Hallbeck, Jan-Ingvar Jönsson, Thomas M. Walz. The pan-ErbB receptor tyrosine kinase inhibitor canertinib induces ErbB-independent apoptosis in human leukemia (HL-60 and U-937) cells. Biochemical and Biophysical Research Communications -BBRC 2010, 393(1):6-10. II. Cecilia Trinks, Emelie A. Severinsson, Birgitta Holmlund, Anna Gréen, Henrik Gréen, Jan-Ingvar Jönsson, Anna-Lotta Hallbeck ,Thomas M. Walz. The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase- mediated cell-death in human T-cell leukemia (Jurkat) cells. Biochemical and Biophysical Research Communications -BBRC 2011, 410(3):422-7. III. Amanda Nordigården, Jenny Zetterblad, Cecilia Trinks, Henrik Gréen, Pernilla Eliasson, Pia Druid, Kourosh Lotfi, Lars Rönnstrand, Thomas M. Walz, Jan-Ingvar Jönsson. Irreversible pan-ERBB inhibitor canertinib elicits anti-leukemic effects and induces the regression of FLT3-ITD transformed cells in mice. British Journal of Haematology, 2011, 155(2):198-208. IV. Cecilia Trinks, Birgitta Holmlund, Jan-Ingvar Jönsson, Thomas M. Walz. Human
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