Skip to main content
SpringerLink
Log in

Molekulardiagnostik zur Therapiestratifizierung des Lungenkarzinoms

Molecular diagnostics of lung cancer for treatment stratification

  • Schwerpunkt
  • Published:
Der Internist Aims and scope Submit manuscript

Zusammenfassung

Weiterhin sind Lungenkarzinome die häufigste tumorbedingte Todesursache in westlichen Industrienationen. Ein hoffnungsvoller therapeutischer Ansatz ist die Entwicklung neuer zielgerichteter Substanzen („targeted drugs“, die spezifisch gegen onkogene Pathomechanismen des nicht-kleinzelligen Bronchialkarzinoms gerichtet sind. So kommen inzwischen bei Adenokarzinomen der Lunge Therapien zum Einsatz, die gegen den epidermalen Wachstumsfaktorrezeptor sowie gegen das transformierende EML4-ALK-Fusionsprotein gerichtet sind. Diese Therapien kommen jedoch fast ausschließlich Patienten zu gute, die nie geraucht haben und relativ seltene Subtypen von Adenokarzinomen aufweisen. Gerichtete therapeutische Optionen für die häufigen Plattenepithelkarzinome der Lunge bei Rauchern gibt es bisher noch nicht. Kürzlich wurden jedoch Amplifikationen des Fibroblasten-Wachstumsfaktor-Rezeptor-Typ-1-Gens als mögliche therapeutische Zielstruktur in dieser Patientengruppe identifiziert. Der vorliegende Beitrag gibt eine Übersicht über die zu Grunde liegenden onkogenen Pathomechanismen sowie die zur Therapiestratifizierung notwendige Molekulardiagnostik des Lungenkarzinoms.

Abstract

Lung tumors continue to be the most frequent cause of cancer-related death in Western industrialized countries. The development of new chemotherapeutic substances that are directed specifically against oncogenic pathomechanisms of non-small cell lung cancer represents a promising therapeutic approach. Meanwhile treatment measures are being employed for pulmonary adenocarcinomas that target the epidermal growth factor receptor and transforming EML4-ALK fusion protein. However, these therapies benefit almost exclusively those patients who have never smoked and manifest relatively rare subtypes of adenocarcinomas. In contrast, targeted therapeutic options for squamous cell carcinomas of the lung frequently found in smokers are still limited, although amplifications of the fibroblast growth factor receptor 1 have recently been identified as possible therapeutic targets in this patient population. This contribution provides an overview of the underlying pathomechanisms and molecular diagnostics needed for treatment stratification.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2
Abb. 3

Literatur

  1. Ahrendt SA, Decker PA, Alawi EA et al (2001) Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer 92:1525–1530

    Article  PubMed  CAS  Google Scholar 

  2. Akimoto T, Hunter NR, Buchmiller L et al (1999) Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas. Clin Cancer Res 5:2884–2890

    PubMed  CAS  Google Scholar 

  3. Alvarez JV, Greulich H, Sellers WR et al (2006) Signal transducer and activator of transcription 3 is required for the oncogenic effects of non-small-cell lung cancer-associated mutations of the epidermal growth factor receptor. Cancer Res 66:3162–3168

    Article  PubMed  CAS  Google Scholar 

  4. Balak MN, Gong Y, Riely GJ et al (2006) Novel D761Y and common secondary T790 M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 12:6494–6501

    Article  PubMed  CAS  Google Scholar 

  5. Batzer AG, Rotin D, Ureña JM et al (1994) Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor. Mol Cell Biol 14:5192–5201

    PubMed  CAS  Google Scholar 

  6. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F et al (2007) Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 67:2643–2648

    Article  PubMed  CAS  Google Scholar 

  7. Bunn PA, Dziadziuszko R, Varella-Garcia M et al (2006) Biological markers for non-small cell lung cancer patient selection for epidermal growth factor receptor tyrosine kinase inhibitor therapy. Clin Cancer Res 12:3652–3656

    Article  PubMed  CAS  Google Scholar 

  8. Chattopadhyay A, Vecchi M, Ji Q et al (1999) The role of individual SH2 domains in mediating association of phospholipase C-gamma1 with the activated EGF receptor. J Biol Chem 274:26091–26097

    Article  PubMed  CAS  Google Scholar 

  9. Chen Z, Ke LD, Yuan XH, Adler-Storthz K (2000) Correlation of cisplatin sensitivity with differential alteration of EGFR expression in head and neck cancer cells. Anticancer Res 20:899–902

    PubMed  CAS  Google Scholar 

  10. Ciardiello F, Tortora G (2001) A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res 7:2958–2970

    PubMed  CAS  Google Scholar 

  11. De Roock W, Piessevaux H, De Schutter J et al (2008) KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 19:508–515

    Google Scholar 

  12. Di Nicolantonio F, Martini M, Molinari F et al (2008) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26:5705–5712

    Article  Google Scholar 

  13. Eberhard DA, Johnson BE, Amler LC et al (2005) Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 23:5900–5909

    Article  PubMed  CAS  Google Scholar 

  14. 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 

  15. Galizia G, Lieto E, De Vita F et al (2007) Cetuximab, a chimeric human mouse anti-epidermal growth factor receptor monoclonal antibody, in the treatment of human colorectal cancer. Oncogene 26:3654–3660

    Article  PubMed  CAS  Google Scholar 

  16. Gandhi J, Zhang J, Xie Y et al (2009) Alterations in Genes of the EGFR Signaling Pathway and Their Relationship to EGFR Tyrosine Kinase Inhibitor Sensitivity in Lung Cancer Cell Lines. PLoS ONE 4:e4576

    Article  PubMed  Google Scholar 

  17. Gee JM, Willsher PC, Kenny FS et al (1999) Endocrine response and resistance in breast cancer: a role for the transcription factor Fos. Int J Cancer 84:54–61

    Article  PubMed  CAS  Google Scholar 

  18. Grunwald V, Hidalgo M (2003) Developing inhibitors of the epidermal growth factor receptor for cancer treatment. J Natl Cancer Inst 95:851–867

    Article  PubMed  Google Scholar 

  19. Han SW, Kim TY, Jeon YK et al (2006) Optimization of patient selection for gefitinib in non-small cell lung cancer by combined analysis of epidermal growth factor receptor mutation, K-ras mutation, and Akt phosphorylation. Clin Cancer Res 12:2538–2544

    Article  PubMed  CAS  Google Scholar 

  20. Heukamp LC, Büttner R (2010) Molekulardiagnostik des Lungenkarzinoms zur Therapiestratifizierung. Pathologe 31: 22–28

    Article  PubMed  CAS  Google Scholar 

  21. Horn L, Pao W (2009) EML4-ALK: honing in on a new target in non-small-cell lung cancer. J Clin Oncol 27:4232–4235

    Article  PubMed  CAS  Google Scholar 

  22. Humphrey PA, Wong AJ, Vogelstein B et al (1988) Amplification and expression of the epidermal growth factor receptor gene in human glioma xenografts. Cancer Res 48:2231–2238

    PubMed  CAS  Google Scholar 

  23. Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5:341–354

    Article  PubMed  CAS  Google Scholar 

  24. Jemal A, Siegel R, Ward E et al (2007) Cancer statistics. CA Cancer J Clin 57:43–66

    Article  PubMed  Google Scholar 

  25. Johnson GL, Vaillancourt RR (1994) Sequential protein kinase reactions controlling cell growth and differentiation. Curr Opin Cell Biol 6:230–238

    Article  PubMed  CAS  Google Scholar 

  26. Jorissen RN, Walker F, Pouliot N et al (2003) Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res 284:31–53

    Article  PubMed  CAS  Google Scholar 

  27. Khambata-Ford S, Garrett CR, Meropol NJ et al (2007) Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25:3230–3237

    Article  PubMed  CAS  Google Scholar 

  28. 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 

  29. Kumar A, Petri ET, Halmos B, Boggon TJ (2008) Structure and clinical relevance of the epidermal growth factor receptor in human cancer. J Clin Oncol 26:1742–1751

    Article  PubMed  CAS  Google Scholar 

  30. Kwatra MM, Bigner DD, Cohn JA (1992) The ligand binding domain of the epidermal growth factor receptor is not required for receptor dimerization. Biochim Biophys Acta 1134:178–181

    Article  PubMed  CAS  Google Scholar 

  31. Li AR, Chitale D, Riely GJ et al (2008) EGFR mutations in lung adenocarcinomas: clinical testing experience and relationship to EGFR gene copy number and immunohistochemical expression. J Mol Diagn 10:242–248

    Article  PubMed  CAS  Google Scholar 

  32. Li S, Schmitz KR, Jeffrey PD et al (2005) Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell 7:301–311

    Article  PubMed  CAS  Google Scholar 

  33. Lièvre A, Bachet JB, Le Corre D et al (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66:3992–3995

    Article  PubMed  Google Scholar 

  34. Lin E, Li L, Guan Y et al (2009) Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers. Mol Cancer Res 7:1466–1476

    Article  PubMed  CAS  Google Scholar 

  35. 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 

  36. Maheswaran S, Sequist LV, Nagrath S et al (2008) Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 359:366–377

    Article  PubMed  CAS  Google Scholar 

  37. Malden LT, Novak U, Kaye AH, Burgess AW (1988) Selective amplification of the cytoplasmic domain of the epidermal growth factor receptor gene in glioblastoma multiforme. Cancer Res 48:2711–2714

    PubMed  CAS  Google Scholar 

  38. Marchetti A, Milella M, Felicioni L et al (2009) Clinical implications of KRAS mutations in lung cancer patients treated with tyrosine kinase inhibitors: an important role for mutations in minor clones. Neoplasia 11:1084–1092

    PubMed  CAS  Google Scholar 

  39. Massarelli E, Varella-Garcia M, Tang X et al (2007) KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin Cancer Res 13:2890–2896

    Article  PubMed  CAS  Google Scholar 

  40. Masui H, Kawamoto T, Sato JD et al (1984) Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 44:1002–1007

    PubMed  CAS  Google Scholar 

  41. Mendelsohn J, Baselga J (2003) Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21:2787–2799

    Article  PubMed  CAS  Google Scholar 

  42. 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 

  43. Moroni M, Veronese S, Benvenuti S et al (2005) Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to anti-EGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 6:279–286

    Article  PubMed  CAS  Google Scholar 

  44. Normanno N, Bianco C, De Luca A et al (2003) Target-based agents against ErbB receptors and their ligands: a novel approach to cancer treatment. Endocr Relat Cancer 10:1–21

    Article  PubMed  CAS  Google Scholar 

  45. Paez JG, Jänne 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 

  46. Pao W, Miller V, Zakowski M et al (2004) EGF receptor gene mutations are common in lung cancers from „never smokers“ and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101:13306–13311

    Article  PubMed  CAS  Google Scholar 

  47. Pao W, Miller VA, Politi KA et al (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73

    Article  PubMed  Google Scholar 

  48. Pao W, Wang TY, Riely GJ et al (2005) KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2:e17

    Article  PubMed  Google Scholar 

  49. Pérez-Soler R, Chachoua A, Hammond LA et al (2004) Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol 22:3238–3247

    Article  PubMed  Google Scholar 

  50. Porebska I, Harlozinska A, Bojarowski T (2000) Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERB B2, ERB B3) in colorectal adenocarcinomas and adenomas. Tumour Biol 21:105–115

    Article  PubMed  CAS  Google Scholar 

  51. Riely GJ, Pao W, Pham D et al (2006) Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res 12:839–844

    Article  PubMed  CAS  Google Scholar 

  52. Rodenhuis S, Slebos RJ, Boot AJ et al (1988) Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung. Cancer Res 48:5738–5741

    PubMed  CAS  Google Scholar 

  53. Rosell R, Moran T, Queralt C et al; Spanish Lung Cancer Group 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 

  54. Salomon DS, Brandt R, Ciardiello F, Normanno N (1995) Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19:183–232

    Article  PubMed  CAS  Google Scholar 

  55. Saltz LRM, Hochster H et al (2001) Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR). Proc Am Soc Clin Oncol 20(3a)

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

    Article  PubMed  CAS  Google Scholar 

  57. Shaw AT, Yeap BY, Mino-Kenudson M et al (2009) Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 27:4247–4253

    Article  PubMed  CAS  Google Scholar 

  58. Sobol RE, Astarita RW, Hofeditz C et al (1987) Epidermal growth factor receptor expression in human lung carcinomas defined by a monoclonal antibody. J Natl Cancer Inst 79:403–407

    PubMed  CAS  Google Scholar 

  59. 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 

  60. Stoscheck CM, King LE (1986) Role of epidermal growth factor in carcinogenesis. Cancer Res 46:1030–1037

    PubMed  CAS  Google Scholar 

  61. Sung T, Miller DC, Hayes RL et al (2000) Preferential inactivation of the p53 tumor suppressor pathway and lack of EGFR amplification distinguish de novo high grade pediatric astrocytomas from de novo adult astrocytomas. Brain Pathol 10:249–259

    Article  PubMed  CAS  Google Scholar 

  62. Tsao MZC, Sakurada A et al (2006) An analysis of the prognostic and predictive importance of K-ras mutation status in the National Cancer Institute of Canada Clinical Trials Group BR.21 study of erlotinib versus placebo in the treatment of non-small cell lung cancer. J Clin Oncol 24:365 s

    Article  Google Scholar 

  63. Weiss J, Sos ML, Seidel D et al (2010) Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1dependency in squamouscell lung cancer. Sci Transl Med 2:62ra93

    PubMed  CAS  Google Scholar 

  64. Woodburn JR (1999) The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther 82:241–250

    Article  PubMed  CAS  Google Scholar 

  65. Yamamoto H, Shigematsu H, Nomura M et al (2008) PIK3CA mutations and copy number gains in human lung cancers. Cancer Res 68:6913–6921

    Article  PubMed  CAS  Google Scholar 

  66. Yamazaki H, Fukui Y, Ueyama Y et al (1988) Amplification of the structurally and functionally altered epidermal growth factor receptor gene (c-erbB) in human brain tumors. Mol Cell Biol 8:1816–1820

    PubMed  CAS  Google Scholar 

  67. Yang CH, Yu CJ, Shih JY et al (2008) Specific EGFR mutations predict treatment outcome of stage IIIB/IV patients with chemotherapy-naive non-small-cell lung cancer receiving first-line gefitinib monotherapy. J Clin Oncol 26:2745–2753

    Article  PubMed  CAS  Google Scholar 

  68. Yousem SA, Nikiforova M, Nikiforov Y (2008) The histopathology of BRAF-V600E-mutated lung adenocarcinoma. Am J Surg Pathol 32:1317–1321

    Article  PubMed  Google Scholar 

  69. Yun CH, Boggon TJ, Li Y et al (2007) Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 11:217–227

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institut für Pathologie, Universitätsklinikum Köln, Kerpener Straße 62, 50924, Köln, Köln

    L.C. Heukamp, J. Wolf & R. Büttner

Authors
  1. L.C. Heukamp
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Büttner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L.C. Heukamp.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Heukamp, L., Wolf, J. & Büttner, R. Molekulardiagnostik zur Therapiestratifizierung des Lungenkarzinoms. Internist 52, 146–154 (2011). https://doi.org/10.1007/s00108-010-2698-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00108-010-2698-y

Schlüsselwörter

Keywords

Search

Navigation