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Thyrosinkinaseinhibitoren in der Onkologie

Tyrosin kinase inhibitors in oncology

  • Arzneimitteltherapie
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An Erratum to this article was published on 10 July 2011

Zusammenfassung

Thyrosinkinaseinhibitoren stellen eine relativ neue Gruppe von Medikamenten in der Onkologie dar. Sie haben jedoch in den letzten Jahren sehr rasch an Bedeutung gewonnen, da sie bei einem Teil der Patienten zu einer sehr ausgeprägten und lang anhaltenden klinischen Verbesserung führen, wie sie mit keiner bisherigen Therapie erreicht werden konnte. Biologisch begründet sich dies darin, dass bei einer Untergruppe von Tumoren bestimmte Thyrosinkinasen das entscheidende Wachstumssignal darstellen. Sehr prominente Beispiele für eine solche Onkogenabhängigkeit stellen die chronische myeloische Leukämie mit der BCR-ABL-Fusion oder das EGFR-mutierte Lungenkarzinom dar, wobei jedoch von zahlreichen weiteren Tumorentitäten in den nächsten Jahren auszugehen ist. Entscheidend für die weitere Entwicklung dieser sehr viel versprechenden Medikamentenklasse ist eine enge Zusammenarbeit zwischen klinischer Forschung in klinischen Studien, präklinischer Grundlagenforschung und exzellenter qualitätskontrollierter molekularer Diagnostik.

Abstract

Thyrosin kinase inhitiors are still are relatively new group of drugs in oncology. But in the past few years they have gained an increasing importance due to the major and long lasting clinical benefit they induce in a subgroup of tumor patients. This success of thyrosin kinase inhibitors is based on the exquisite importance of thyrosin kinases for growth and survival of tumor cells. Prominent examples of such an oncogene dependency are the BCR-ABL fusion in chronic myeloid leukemia or EGFR mutations in lung adenocarcinoma. Many further tumor entities with clinically tractable oncogene dependencies can be expected in the upcoming years. An intense interaction between clinical science in clinical trials, preclinical research and excellent molecular quality controlled diagnostics is crucial for the further development.

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Literatur

  1. Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411:355–365

    Article  PubMed  CAS  Google Scholar 

  2. Cappuzzo F, Hirsch FR, E. Rossi E et al (2005) Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 97:643–655

    Article  PubMed  CAS  Google Scholar 

  3. Chan S, Scheulen ME, Johnston S et al (2005) Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 23:5314–5322

    Article  PubMed  CAS  Google Scholar 

  4. Cobleigh MA, Vogel CL, Tripathy D et al (1999) Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639–2648

    PubMed  CAS  Google Scholar 

  5. Cohen MH, Farrell A, Justice R et al (2009) Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Oncologist 14:174–180

    Article  PubMed  CAS  Google Scholar 

  6. Dalgliesh GL, Furge K, Greenman C et al (2010) Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463:360–363

    Article  PubMed  CAS  Google Scholar 

  7. DeMatteo RP, Lewis JJ, Leung D et al (2000) Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 231:51–58

    Article  PubMed  CAS  Google Scholar 

  8. Druker BJ, Guilhot F, O’Brien SG et al (2006) Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355:2408–2417

    Article  PubMed  CAS  Google Scholar 

  9. Druker BJ, Sawyers CL, Kantarjian H et al (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038–1042

    Article  PubMed  CAS  Google Scholar 

  10. Eberhard DA, Giaccone G, Johnson BE (2008) Biomarkers of response to epidermal growth factor receptor inhibitors in Non-Small-Cell Lung Cancer Working Group: standardization for use in the clinical trial setting. J Clin Oncol 26:983–994

    Article  PubMed  Google Scholar 

  11. Engelman JA, Zejnullahu K, Mitsudomi T et al (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039–1043

    Article  PubMed  CAS  Google Scholar 

  12. Gomez HL, Doval DC, Chavez MA et al (2008) Efficacy and safety of lapatinib as first-line therapy for ErbB2-amplified locally advanced or metastatic breast cancer. J Clin Oncol 26:2999–3005

    Article  PubMed  CAS  Google Scholar 

  13. Greenman C, Stephens P, Smith R et al (2007) Patterns of somatic mutation in human cancer genomes. Nature 446:153–158

    Article  PubMed  CAS  Google Scholar 

  14. Greenman C, Wooster R, Futreal PA et al (2006) Statistical analysis of pathogenicity of somatic mutations in cancer. Genetics 173:2187–2198

    Article  PubMed  CAS  Google Scholar 

  15. Hartmann JT, Haap M, Kopp HG et al (2009) Tyrosine kinase inhibitors – a review on pharmacology, metabolism and side effects. Curr Drug Metab 10:470–481

    Article  PubMed  CAS  Google Scholar 

  16. Heinrich MC, Corless CL, Demetri GD et al (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342–4349

    Article  PubMed  CAS  Google Scholar 

  17. Heinrich MC, Corless CL, Duensing A et al (2003) PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299:708–710

    Article  PubMed  CAS  Google Scholar 

  18. Hilberg F, Roth GJ, Krssak M et al (2008) BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 68:4774–4782

    Article  PubMed  CAS  Google Scholar 

  19. Hirota S, Isozaki K, Moriyama Y et al (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279:577–580

    Article  PubMed  CAS  Google Scholar 

  20. Kantarjian H, Shah NP, Hochhaus A et al (2010) Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 362:2260–2270

    Article  PubMed  CAS  Google Scholar 

  21. Kobayashi S, Boggon TJ, Dayaram T et al (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786–792

    Article  PubMed  CAS  Google Scholar 

  22. Kwak EL, Bang YJ, Camidge DR et al (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693–1703

    Article  PubMed  CAS  Google Scholar 

  23. Loriot Y, Perlemuter G, Malka D et al (2008) Drug insight: gastrointestinal and hepatic adverse effects of molecular-targeted agents in cancer therapy. Nat Clin Pract Oncol 5:268–278

    Article  PubMed  CAS  Google Scholar 

  24. Lynch TJ, Bell DW, Sordella R et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139

    Article  PubMed  CAS  Google Scholar 

  25. Maemondo M, Inoue A, Kobayashi K et al (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362:2380–2388

    Article  PubMed  CAS  Google Scholar 

  26. Maira SM, Stauffer F, Brueggen J et al (2008) Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 7:1851–1863

    Article  PubMed  CAS  Google Scholar 

  27. Mok TS, Wu YL, Thongprasert S et al (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957

    Article  PubMed  CAS  Google Scholar 

  28. Paez JG, Janne PA, Lee JC et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500

    Article  PubMed  CAS  Google Scholar 

  29. Parsons DW, Jones S, Zhang X et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812

    Article  PubMed  CAS  Google Scholar 

  30. Petak I, Schwab R, Orfi L et al (2010) Integrating molecular diagnostics into anticancer drug discovery. Nat Rev Drug Discov 9:523–535

    Article  PubMed  CAS  Google Scholar 

  31. Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672

    Article  PubMed  CAS  Google Scholar 

  32. Pleasance ED, Cheetham RK, Stephens PJ et al (2010) A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463:191–196

    Article  PubMed  CAS  Google Scholar 

  33. Pleasance ED, Stephens PJ, O’Meara S et al (2010) A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 463:184–190

    Article  PubMed  CAS  Google Scholar 

  34. Regales L, Gong Y, Shen R et al (2009) Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J Clin Invest 119:3000–3010

    PubMed  CAS  Google Scholar 

  35. Rosell R, Moran T, Queralt C et al (2009) Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 361:958–967

    Article  PubMed  CAS  Google Scholar 

  36. Saglio G, Kim DW, Issaragrisil S et al (2010) Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362:2251–2259

    Article  PubMed  CAS  Google Scholar 

  37. Sandler A, Gray R, Perry MC et al (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550

    Article  PubMed  CAS  Google Scholar 

  38. Schiller JH, Harrington D, Belani CP et al (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92–98

    Article  PubMed  CAS  Google Scholar 

  39. Sharma SV, Bell DW, Settleman J et al (2007) Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 7:169–181

    Article  PubMed  CAS  Google Scholar 

  40. Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132

    Article  PubMed  CAS  Google Scholar 

  41. Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792

    Article  PubMed  CAS  Google Scholar 

  42. Smalley KS, Flaherty KT (2009) Integrating BRAF/MEK inhibitors into combination therapy for melanoma. Br J Cancer 100:431–435

    Article  PubMed  CAS  Google Scholar 

  43. Soda M, Choi YL, Enomoto M et al (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561–566

    Article  PubMed  CAS  Google Scholar 

  44. Soda M, Takada S, Takeuchi K et al (2008) A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci U S A 105:19893–19897

    Article  PubMed  CAS  Google Scholar 

  45. Sos ML, Koker M, Weir BA et al (2009) PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res 69:3256–3261

    Article  PubMed  CAS  Google Scholar 

  46. Tsao MS, Sakurada A, Cutz JC et al (2005) Erlotinib in lung cancer – molecular and clinical predictors of outcome. N Engl J Med 353:133–144

    Article  PubMed  CAS  Google Scholar 

  47. Untch M, Rezai M, Loibl S et al (2010) Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. J Clin Oncol 28:2024–2031

    Article  PubMed  CAS  Google Scholar 

  48. Weinstein IB (2002) Cancer. Addiction to oncogenes – the Achilles heal of cancer. Science 297:63–64

    Article  PubMed  CAS  Google Scholar 

  49. Weiss J, Sos ML, Seidel D et al (2010) Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med 2:62ra93

    PubMed  CAS  Google Scholar 

  50. Wood LD, Parsons DW, Jones S et al (2007) The genomic landscapes of human breast and colorectal cancers. Science 318:1108–1113

    Article  PubMed  CAS  Google Scholar 

  51. Yap TA, Vidal L, Adam J et al (2010) Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J Clin Oncol 28:3965–3972

    Article  PubMed  CAS  Google Scholar 

  52. Zou HY, Li Q, Lee JH et al (2007) An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res 67:4408–4417

    Article  PubMed  CAS  Google Scholar 

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Interessenkonflikt

Der korrespondierende Autor gibt an, dass kein Interessenkonflikt besteht.

Prof. Hallek: Honorare von Roche und Mundipharma.

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Authors and Affiliations

  1. Centrum für Integrierte Onkologie Köln-Bonn, Klinik I für Innere Medizin, Universitätsklinik Köln, Kerpenerstraße 62, 50924, Köln, Deutschland

    T. Zander & M. Hallek

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  1. T. Zander
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  2. M. Hallek
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Correspondence to T. Zander.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s00108-011-2886-4

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Zander, T., Hallek, M. Thyrosinkinaseinhibitoren in der Onkologie. Internist 52, 595–600 (2011). https://doi.org/10.1007/s00108-011-2818-3

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