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Effect of Genetic Kinome Alterations on the Response of Cancer Cells to SUTENT Therapy

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Effect of Genetic Kinome Alterations on the Response of Cancer Cells to SUTENT Therapy TECHNISCHE UNIVERSITÄT MÜNCHEN Fachgebiet für Entwicklungsbiologie der Pflanzen Effect of Genetic Kinome Alterations on the Response of Cancer Cells to SUTENT Therapy Torsten Winkler Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften (Dr. rer. nat.) genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr. C. Schwechheimer Prüfer der Dissertation: 1. Univ.-Prof. Dr. K. Schneitz 2. Hon.-Prof. Dr. A. Ullrich (Eberhard-Karls-Universität Tübingen) Die Dissertation wurde am 23.11.2010 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 08.02.2011 angenommen. ERKLÄRUNG Ich erkläre an Eides statt, dass ich die der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München vorgelegte Dissertationsarbeit mit dem Titel: Effect of Genetic Kinome Alterations on the Response of Cancer Cells to SUTENT Therapy angefertigt am Max-Planck-Institut für Biochemie in Martinsried unter der Anleitung und Betreuung durch Herrn Professor Dr. Axel Ullrich (MPI für Biochemie, Martinsried) und Herrn Professor Dr. Kay Schneitz (Fachgebiet Entwicklungsbiologie der Pflanzen, TU München) ohne sonstige Hilfe verfasst und bei der Abfassung nur die gemäß § 6 Abs. 5 angegebenen Hilfsmittel benutzt habe. Ich habe die Dissertation in dieser oder ähnlicher Form in keinem anderen Prüfungsverfahren als Prüfungsleistung vorgelegt. Die Promotionsordnung der Technischen Universität München ist mir bekannt. München, den ______________________ _____________________________________ Torsten Winkler For Sylvia and Lara C o n t e n t s | 4 1. Contents 2. Summary .................................................................................................................................. 7 3. Zusammenfassung ................................................................................................................ 8 4. Abbreviations ......................................................................................................................... 9 5. Introduction ........................................................................................................................ 12 5.1 Cancer – A disease with many faces ............................................................................................... 12 5.1.1 Characterization of cancer........................................................................................................ 13 5.1.2 Development of malignant tumors at the molecular level ........................................... 15 5.2 Protein kinases – Key players in cancer development, progression, and therapy ...... 19 5.2.1 Involvement of protein kinases in cancer .......................................................................... 20 5.2.2 Protein kinases as targets for cancer therapy .................................................................. 23 5.3 The small molecule inhibitor sunitinib malate (SU12248, SUTENT®) ............................. 27 5.3.1 Evolution of sunitinib malate – from single-targeting to multi-targeting ............. 27 5.3.2 The spectrum of target proteins inhibited by sunitinib malate ................................. 29 5.4 Genetic alterations in cancer ............................................................................................................ 31 5.4.1 Genetic alterations – friend and foe of cancer therapy ................................................. 31 5.4.2 Genetic alterations in tumors treated with sunitinib malate ..................................... 32 6. Aims of this PhD thesis .................................................................................................... 34 7. Materials and Methods .................................................................................................... 35 7.1 Materials ................................................................................................................................................... 35 7.1.1 Laboratory chemicals, biochemicals and inhibitors ....................................................... 35 C o n t e n t s | 5 7.1.2 Enzymes ........................................................................................................................................... 36 7.1.3 Kits and other materials ............................................................................................................ 36 7.1.4 Growth factors and ligands ...................................................................................................... 36 7.2 Cell culture media ................................................................................................................................. 37 7.3 Stock solutions and commonly used buffers .............................................................................. 37 7.4 Cell lines .................................................................................................................................................... 39 7.5 Antibodies ................................................................................................................................................ 43 7.5.1 Primary antibodies ........................................................................................................................... 43 7.5.2 Secondary antibodies ................................................................................................................. 43 7.6 Oligonucleotides .................................................................................................................................... 44 7.6.1 siRNA oligonucleotides .............................................................................................................. 44 7.6.2 Primers ............................................................................................................................................. 44 7.7 Methods .................................................................................................................................................... 44 7.7.1 Cellular Assays .............................................................................................................................. 44 7.7.2 Molecular methods ...................................................................................................................... 46 7.7.3 Databases and Statistics ............................................................................................................ 48 8. Results ................................................................................................................................... 49 8.1 Proof of principle: Influence of mutations in EGFR on the response to gefitinib treatment ......................................................................................................................................................... 49 8.1.1 Allele-dependent influence of EGFRG719S and EGFRP753S on the gefitinib-induced inhibition of proliferation .................................................................................................................... 51 8.1.2 Influence of EGFRG719S on the efficacy of gefitinib at the molecular level .............. 54 8.2 Influence of genetic alterations on the response to sunitinib treatment ........................ 55 8.2.1 Selection of genetic alterations ............................................................................................... 56 8.2.2 Analysis of the sunitinib sensitivity spectrum.................................................................. 57 8.2.3 Statistical analysis of the distribution of alleles ............................................................... 66 8.2.4 Verification of candidate selection ........................................................................................ 69 C o n t e n t s | 6 8.2.5 Influence of identified candidates on the response to sunitinib treatment .......... 73 8.2.6 General role of TYK2 in cancer ............................................................................................... 86 8.2.7 Influence of RON1335R/G and TYK2684I/S at the cellular level ........................................ 88 8.2.8 Mode of TYK2 action ................................................................................................................... 92 9. Discussion .................................................................................................................................... 95 10. References ............................................................................................................................... 100 11. Acknowledgements.............................................................................................................. 117 S u m m a r y | 7 2. Summary Genetic alterations are widely known to influence the etiopathology of tumor development as well as the therapeutic outcome of cancer treatment. The anti-cancer drug SUTENT® (sunitinib malate, SU12248), an orally available multi-targeted small molecule inhibitor, has been approved for the treatment of gastrointestinal stromal tumors (GIST) and metastatic renal cell carcinoma (mRCC). So far, only a few genetic alterations in patients with GIST are known to impair the effect of the drug. Since
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