Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer — Sci TM

Sci Transl Med 15 December 2010:
Vol. 2, Issue 62, p. 62ra93
DOI: 10.1126/scitranslmed.3001451

* Research Article

Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer

1. Jonathan Weiss1,*,
2. Martin L. Sos1,*† ,
3. Danila Seidel1,2,*,
4. Martin Peifer1,
5. Thomas Zander3,
6. Johannes M. Heuckmann1,
7. Roland T. Ullrich1,
8. Roopika Menon4,
9. Sebastian Maier4,
10. Alex Soltermann5,
11. Holger Moch5,
12. Patrick Wagener6,
13. Florian Fischer1,
14. Stefanie Heynck1,
15. Mirjam Koker1,
16. Jakob Schöttle1,
17. Frauke Leenders1,2,
18. Franziska Gabler1,2,
19. Ines Dabow1,2,
20. Silvia Querings1,
21. Lukas C. Heukamp7,
22. Hyatt Balke-Want1,
23. Sascha Ansén3,
24. Daniel Rauh8,
25. Ingelore Baessmann9,
26. Janine Altmüller9,
27. Zoe Wainer10,
28. Matthew Conron10,
29. Gavin Wright10,
30. Prudence Russell11,
31. Ben Solomon12,
32. Elisabeth Brambilla13,14,
33. Christian Brambilla13,14,
34. Philippe Lorimier13,
35. Steinar Sollberg15,
36. Odd Terje Brustugun16,17,
37. Walburga Engel-Riedel18,
38. Corinna Ludwig18,
39. Iver Petersen19,
40. Jörg Sänger20,
41. Joachim Clement21,
42. Harry Groen22,
43. Wim Timens23,
44. Hannie Sietsma23,
45. Erik Thunnissen24,
46. Egbert Smit25,
47. Daniëlle Heideman24,
48. Federico Cappuzzo26,
49. Claudia Ligorio27,
50. Stefania Damiani27,
51. Michael Hallek3,28,
52. Rameen Beroukhim29,30,31,32,
53. William Pao33,
54. Bert Klebl34,
55. Matthias Baumann34,
56. Reinhard Buettner7,
57. Karen Ernestus35,
58. Erich Stoelben18,
59. Jürgen Wolf2,3,
60. Peter Nürnberg8,28,
61. Sven Perner4 and
62. Roman K. Thomas1,2,3,7,†

+ Author Affiliations

1. 1Max Planck Institute for Neurological Research, Klaus-Joachim-Zülch Laboratories of the Max Planck Society and the Medical Faculty of the University of Cologne, 50931 Cologne, Germany.
2. 2Laboratory of Translational Cancer Genomics, Center of Integrated Oncology Köln-Bonn, University of Cologne, 50924 Cologne, Germany.
3. 3Department I of Internal Medicine and Center of Integrated Oncology Köln-Bonn, University of Cologne, 50924 Cologne, Germany.
4. 4Institute of Pathology, Comprehensive Cancer Center, University Hospital Tübingen, 72076 Tübingen, Germany.
5. 5Institute for Surgical Pathology, University Hospital Zurich, 8091 Zurich, Switzerland.
6. 6Department of Surgery, Weill Medical College, Cornell University, New York, NY 10065, USA.
7. 7Institute of Pathology, University of Bonn, 53123 Bonn, Germany.
8. 8Chemical Genomics Center, Max Planck Society, 44227 Dortmund, Germany.
9. 9Cologne Center for Genomics and Institute for Genetics, University of Cologne, 50931 Cologne, Germany.
10. 10Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, 3002 Victoria, Australia.
11. 11Department of Pathology, St. Vincent’s Hospital, Melbourne, 3065 Victoria, Australia.
12. 12Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, 3002 Victoria, Australia.
13. 13Department of Pathology, Université Joseph Fourier, 38041 Grenoble, France.
14. 14Institut Albert Bonniot INSERM U823, Université Joseph Fourier, 38042 Grenoble, France.
15. 15Department of Thoracic Surgery, Rikshospitalet, Oslo University Hospital, 0027 Oslo, Norway.
16. 16Department of Radiation Biology, Norwegian Radium Hospital, N-0310 Oslo, Norway.
17. 17Department of Oncology, Radiumhospitalet, Oslo University Hospital, N-0310 Oslo, Norway.
18. 18Thoracic Surgery, Lungenklinik Merheim, Kliniken der Stadt Köln gGmbH, 51109 Cologne, Germany.
19. 19Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University, 07743 Jena, Germany.
20. 20Institute for Pathology Bad Berka, 99438 Bad Berka, Germany.
21. 21Department for Internal Medicine II, University Clinic Jena, Friedrich-Schiller University, 07740 Jena, Germany.
22. 22Department of Pulmonary Diseases, University Medical Centre Groningen, 9713 GZ Groningen, Netherlands.
23. 23Department of Pathology, University Medical Centre Groningen, 9713 GZ Groningen, Netherlands.
24. 24Department of Pathology, VU University Medical Center Amsterdam, 1007 MB Amsterdam, Netherlands.
25. 25Department of Pulmonary Diseases, VU University Medical Center Amsterdam, 1007 MB Amsterdam, Netherlands.
26. 26Department of Medical Oncology, Ospedale Civile, 57100 Livorno, Italy.
27. 27Department of Haematology and Oncologic Science, University Hospital Bologna, 40138 Bologna, Italy.
28. 28Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
29. 29Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
30. 30Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA.
31. 31Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
32. 32Cancer Program, Broad Institute, Cambridge, MA 02115, USA.
33. 33Vanderbilt-Ingram Cancer Center, Nashville, TN 37212, USA.
34. 34Lead Discovery Center GmbH, 44227 Dortmund, Germany.
35. 35Department of Pathology, Hospital Merheim, Kliniken der Stadt Köln gGmbH, 51109 Cologne, Germany.

1. †To whom correspondence should be addressed. E-mail: martin.sos@nf.mpg.de (M.L.S.); nini@nf.mpg.de (R.K.T.)

Abstract

Lung cancer remains one of the leading causes of cancer-related death in developed countries. Although lung adenocarcinomas with EGFR mutations or EML4-ALK fusions respond to treatment by epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibition, respectively, squamous cell lung cancer currently lacks therapeutically exploitable genetic alterations. We conducted a systematic search in a set of 232 lung cancer specimens for genetic alterations that were therapeutically amenable and then performed high-resolution gene copy number analyses. We identified frequent and focal fibroblast growth factor receptor 1 (FGFR1) amplification in squamous cell lung cancer (n = 155), but not in other lung cancer subtypes, and, by fluorescence in situ hybridization, confirmed the presence of FGFR1 amplifications in an independent cohort of squamous cell lung cancer samples (22% of cases). Using cell-based screening with the FGFR inhibitor PD173074 in a large (n = 83) panel of lung cancer cell lines, we demonstrated that this compound inhibited growth and induced apoptosis specifically in those lung cancer cells carrying amplified FGFR1. We validated the FGFR1 dependence of FGFR1-amplified cell lines by FGFR1 knockdown and by ectopic expression of an FGFR1-resistant allele (FGFR1V561M), which rescued FGFR1-amplified cells from PD173074-mediated cytotoxicity. Finally, we showed that inhibition of FGFR1 with a small molecule led to significant tumor shrinkage in vivo. Thus, focal FGFR1 amplification is common in squamous cell lung cancer and associated with tumor growth and survival, suggesting that FGFR inhibitors may be a viable therapeutic option in this cohort of patients.

Footnotes

* ↵* These authors contributed equally to this work.
* Citation: J. Weiss, M. L. Sos, D. Seidel, M. Peifer, T. Zander, J. M. Heuckmann, R. T. Ullrich, R. Menon, S. Maier, A. Soltermann, H. Moch, P. Wagener, F. Fischer, S. Heynck, M. Koker, J. Schöttle, F. Leenders, F. Gabler, I. Dabow, S. Querings, L. C. Heukamp, H. Balke-Want, S. Ansén, D. Rauh, I. Baessmann, J. Altmüller, Z. Wainer, M. Conron, G. Wright, P. Russell, B. Solomon, E. Brambilla, C. Brambilla, P. Lorimier, S. Sollberg, O. T. Brustugun, W. Engel-Riedel, C. Ludwig, I. Petersen, J. Sänger, J. Clement, H. Groen, W. Timens, H. Sietsma, E. Thunnissen, E. Smit, D. Heideman, F. Cappuzzo, C. Ligorio, S. Damiani, M. Hallek, R. Beroukhim, W. Pao, B. Klebl, M. Baumann, R. Buettner, K. Ernestus, E. Stoelben, J. Wolf, P. Nürnberg, S. Perner, R. K. Thomas, Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci. Transl. Med. 2, 62ra93 (2010).

* Copyright © 2010, American Association for the Advancement of Science

Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer — Sci TM




TABAQUISMO
Actualidad Ultimas noticias - JANOes y agencias -
Identifican una diana terapéutica para el cáncer de pulmón inducido por el tabaquismo

JANO.es y agencias · 16 Diciembre 2010 09:52

El descubrimiento apunta a cambios genéticos en los pulmones de fumadores, que pueden ser alterados por vías terapéuticas.


Investigadores del Instituto Max Planck de Investigación Neurológica en Colonia, Alemania, han descubierto una diana terapéutica para un tipo de cáncer de pulmón que se produce en los fumadores y es resistente a la mayoría de fármacos para el cáncer. Los descubrimientos apuntan por primera vez a cambios genéticos en los pulmones de fumadores que pueden ser alterados por vías terapéuticas y podría conducir a nuevas terapias para estos pacientes. Los resultados del estudio se publican en la revista Science Translational Medicine.

Los tratamientos para los adenocarcinomas de pulmón, que afectan principalmente a quienes nunca han fumado, inhiben ciertas proteínas mutadas en grupos de pacientes con la enfermedad. Sin embargo, los fumadores desarrollan frecuentemente otro tipo de cáncer de pulmón, conocido como cáncer de pulmón de células escamosas, para el que no existen buenas dianas genéticas. Este tipo de cáncer pulmonar tiende a responder mal a la quimioterapia y la radioterapia.

En su trabajo, los investigadores, dirigidos por Roman Thomas, han identificado el gen FGFR1 como un nuevo sospechoso en el cáncer pulmonar de células escamosas.

Los investigadores estaban creando perfiles genómicos de un gran conjunto de células del cáncer de pulmón cuando descubrieron que las muestras de cáncer de pulmón de células escamosas contenían muchas copias del gen FGFR1. Además, la inhibición del gen FGFR1 reducía los tumores en un modelo de ratón con cáncer de pulmón de células escamosas.

Los resultados apuntan a FGFR1 como una característica distintiva de los cánceres de pulmón de células escamosas y a una diana para tratar el cáncer de pulmón inducido por el tabaquismo. El próximo año comenzará un ensayo clínico para evaluar un fármaco diseñado para dirigirse al gen FGFR1 en los pacientes.


Sci Transl Med 15 December 2010; Vol. 2, Issue 62, p. 62ra93
Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer — Sci TM

Instituto Max Planck de Investigación Neurológica
Max Planck Society - Max Planck Institute for Neurological Research with Klaus-Joachim-Zülch-Laboratories of the Max Planck Society and the Faculty of Medicine of the University of Cologne

Actualidad Ultimas noticias - JANOes y agencias - Identifican una diana terapeutica para el cancer de pulmon inducido por el tabaquismo - JANO.es - ELSEVIER