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

被引：630

作者：

Weiss, Jonathan ^{[1
,2
]}

Sos, Martin L. ^{[1
,2
]}

Seidel, Danila ^{[1
,2
,3
]}

Peifer, Martin ^{[1
,2
]}

Zander, Thomas ^{[4
]}

Heuckmann, Johannes M. ^{[1
,2
]}

Ullrich, Roland T. ^{[1
,2
]}

Menon, Roopika ^{[5
]}

Maier, Sebastian ^{[5
]}

Soltermann, Alex ^{[6
]}

Moch, Holger ^{[6
]}

Wagener, Patrick ^{[7
]}

Fischer, Florian ^{[1
,2
]}

Heynck, Stefanie ^{[1
,2
]}

Koker, Mirjam ^{[1
,2
]}

Schoettle, Jakob ^{[1
,2
]}

Leenders, Frauke ^{[1
,2
,3
]}

Gabler, Franziska ^{[1
,2
,3
]}

Dabow, Ines ^{[1
,2
,3
]}

Querings, Silvia ^{[1
,2
]}

Heukamp, Lukas C. ^{[8
]}

Balke-Want, Hyatt ^{[1
,2
]}

Ansen, Sascha ^{[4
]}

Rauh, Daniel ^{[9
]}

Baessmann, Ingelore ^{[10
,11
]}

Altmueller, Janine ^{[10
,11
]}

Wainer, Zoe ^{[12
]}

Conron, Matthew ^{[12
]}

Wright, Gavin ^{[12
]}

Russell, Prudence ^{[13
]}

Solomon, Ben ^{[14
]}

Brambilla, Elisabeth ^{[15
,16
]}

Brambilla, Christian ^{[15
,16
]}

Lorimier, Philippe ^{[15
]}

Sollberg, Steinar ^{[17
]}

Brustugun, Odd Terje ^{[18
,19
]}

Engel-Riedel, Walburga ^{[20
]}

Ludwig, Corinna ^{[20
]}

Petersen, Iver ^{[21
]}

Saenger, Joerg ^{[22
]}

Clement, Joachim ^{[23
]}

Groen, Harry ^{[24
]}

Timens, Wim ^{[25
]}

Sietsma, Hannie ^{[25
]}

Thunnissen, Erik ^{[26
]}

Smit, Egbert ^{[27
]}

Heideman, Danielle ^{[26
]}

Cappuzzo, Federico ^{[28
]}

Ligorio, Claudia ^{[29
]}

Damiani, Stefania ^{[29
]}

机构：

[1] Univ Cologne, Max Planck Inst Neurol Res, Klaus Joachim Zulch Labs, Max Planck Soc, D-50931 Cologne, Germany

[2] Univ Cologne, Fac Med, D-50931 Cologne, Germany

[3] Univ Cologne, Ctr Integrated Oncol Koln Bonn, Lab Translat Canc Genom, D-50924 Cologne, Germany

[4] Univ Cologne, Dept Internal Med, D-50924 Cologne, Germany

[5] Univ Tubingen Hosp, Ctr Comprehens Canc, Inst Pathol, D-72076 Tubingen, Germany

[6] Univ Zurich Hosp, Inst Surg Pathol, CH-8091 Zurich, Switzerland

[7] Cornell Univ, Weill Med Coll, Dept Surg, New York, NY 10065 USA

[8] Univ Bonn, Inst Pathol, D-53123 Bonn, Germany

[9] Max Planck Soc, Chem Genom Ctr, D-44227 Dortmund, Germany

[10] Univ Cologne, Cologne Ctr Genom, D-50931 Cologne, Germany

[11] Univ Cologne, Inst Genet, D-50931 Cologne, Germany

[12] Peter MacCallum Canc Inst, Dept Surg Oncol, Melbourne, Vic 3002, Australia

[13] St Vincents Hosp, Dept Pathol, Fitzroy, Vic 3065, Australia

[14] Peter MacCallum Canc Ctr, Dept Haematol & Oncol, Melbourne, Vic 3002, Australia

[15] Univ Grenoble 1, Dept Pathol, F-38041 Grenoble, France

[16] Univ Grenoble 1, Inst Albert Bonniot, INSERM, U823, F-38042 Grenoble, France

[17] Oslo Univ Hosp, Dept Thorac Surg, Rikshosp, N-0027 Oslo, Norway

[18] Norwegian Radium Hosp, Dept Radiat Biol, N-0310 Oslo, Norway

[19] Oslo Univ Hosp, Dept Oncol, Radiumhosp, N-0310 Oslo, Norway

[20] Kliniken Stadt Koln gGmbH, Lungenklin Merheim, D-51109 Cologne, Germany

[21] Univ Jena, Jena Univ Hosp, Inst Pathol, D-07743 Jena, Germany

[22] Inst Pathol Bad Berka, D-99438 Bad Berka, Germany

[23] Univ Jena, Univ Clin Jena, Dept Internal Med 2, D-07740 Jena, Germany

[24] Univ Groningen, Univ Med Ctr Groningen, Dept Pulm Dis, NL-9713 GZ Groningen, Netherlands

[25] Univ Med Ctr Groningen, Dept Pathol, NL-9713 GZ Groningen, Netherlands

[26] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, NL-1007 MB Amsterdam, Netherlands

[27] Vrije Univ Amsterdam, Med Ctr, Dept Pulm Dis, NL-1007 MB Amsterdam, Netherlands

[28] Osped Civile, Dept Med Oncol, I-57100 Livorno, Italy

[29] Univ Hosp Bologna, Dept Haematol & Oncol Sci, I-40138 Bologna, Italy

[30] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[31] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[32] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[33] Broad Inst, Canc Program, Cambridge, MA 02115 USA

[34] Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA

[35] Lead Discovery Ctr GmbH, D-44227 Dortmund, Germany

[36] Kliniken Stadt Koln gGmbH, Hosp Merheim, Dept Pathol, D-51109 Cologne, Germany

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2010年 / 2卷 / 62期

关键词：

KINASE INHIBITORS; BREAST-CANCER; MUTATIONS; GEFITINIB; SENSITIVITY; CARCINOMAS; TUMOR; GENE; ADENOCARCINOMA; IDENTIFICATION;

D O I：

10.1126/scitranslmed.3001451

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 (FGFR1(V561M)), 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.

引用

页数：7

共 50 条

[1] Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer (vol 2, 62ra93, 2010)
Weiss, J.
Sos, M. L.
Seidel, D.
Peifer, M.
Zander, T.
Heuckmann, J. M.
Ullrich, R. T.
Menon, R.
Maier, S.
Soltermann, A.
Moch, H.
Wagener, P.
Fischer, F.
Heynck, S.
Koker, M.
Schoettle, J.
Leenders, F.
Gabler, F.
Dabow, I.
Querings, S.
Heukamp, L. C.
Balke-Want, H.
Ansen, S.
Rauh, D.
Baessmann, I.
Altmueller, J.
Wainer, Z.
Conron, M.
Wright, G.
Russell, P.
Solomon, B.
Brambilla, E.
Brambilla, C.
Lorimier, P.
Sollberg, S.
Brustugun, O. T.
Engel-Riedel, W.
Ludwig, C.
Petersen, I.
Saenger, J.
Clement, J.
Groen, H.
Timens, W.
Sietsma, H.
Thunnissen, E.
Smit, E.
Heideman, D.
Cappuzzo, F.
Ligorio, C.
Damiani, S.
SCIENCE TRANSLATIONAL MEDICINE, 2012, 4 (130)
[2] Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer (vol 2, 62ra93, 2010)
Weiss, J.
Sos, M. L.
Seidel, D.
Peifer, M.
Zander, T.
Heuckmann, J. M.
Ullrich, R. T.
Menon, R.
Maier, S.
Soltermann, A.
Moch, H.
Wagener, P.
Fischer, F.
Heynck, S.
Koker, M.
Schoettle, J.
Leenders, F.
Gabler, F.
Dabow, I.
Querings, S.
Heukamp, L. C.
Balke-Want, H.
Ansen, S.
Rauh, D.
Baessmann, I.
Altmueller, J.
Wainer, Z.
Conron, M.
Wright, G.
Russell, P.
Solomon, B.
Brambilla, E.
Brambilla, C.
Lorimier, P.
Sollberg, S.
Brustugun, O. T.
Engel-Riedel, W.
Ludwig, C.
Petersen, I.
Saenger, J.
Clement, J.
Groen, H.
Timens, W.
Sietsma, H.
Thunnissen, E.
Smit, E.
Heideman, D.
Cappuzzo, F.
Ligorio, C.
Damiani, S.
SCIENCE TRANSLATIONAL MEDICINE, 2011, 3 (66)
[3] Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer (vol 3, 66er5, 2011)
Weiss, J.
Sos, L.
Seidel, D.
Peifer, M.
Zander, T.
Heuckmann, J. M.
Ullrich, R. T.
Menon, R.
Maier, S.
Soltermann, A.
Moch, H.
Wagener, P.
Fischer, F.
Heynck, S.
Koker, M.
Schoettle, J.
Leenders, F.
Gabler, F.
Dabow, I.
Querings, S.
Heukamp, L. C.
Balke-Want, H.
Ansen, S.
Rauh, D.
Baessmann, I.
Altmueller, J.
Wainer, Z.
Conron, M.
Wright, G.
Russell, P.
Solomon, B.
Brambilla, E.
Brambilla, C.
Lorimier, P.
Sollberg, S.
Brustugun, O. T.
Engel-Riedel, W.
Ludwig, C.
Petersen, I.
Saenger, J.
Clement, J.
Groen, H.
Timens, W.
Sietsma, H.
Thunnissen, E.
Smit, E.
Heideman, D.
Cappuzzo, F.
Ligorio, C.
Damiani, S.
SCIENCE TRANSLATIONAL MEDICINE, 2010, 2 (62)
[4] Frequent High-level Amplification of Fgfr1 Associates With Therapeutically Tractable Fgfr1 Dependency in Squamous-cell Lung Cancer: A First Result of The Clinical Lung Cancer Genome Project Initiative
Thomas, R.
JOURNAL OF THORACIC ONCOLOGY, 2010, 5 (12) : S516 - S516
[5] Fgfr1 Amplification In Squamous Cell Lung Cancer
Gadgeel, S.
Bepler, G.
Schwartz, A.
Land, S.
Bollig-Fischer, A.
Murphy, V.
Cote, M.
JOURNAL OF THORACIC ONCOLOGY, 2012, 7 (09) : S221 - S222
[6] FGFR1 amplification in squamous cell lung cancers
Cote, Michele L.
Bepler, Gerold
Land, Susan
Bollig-Fischer, Aliccia
Schwartz, Ann G.
Gadgeel, Shirish M.
JOURNAL OF CLINICAL ONCOLOGY, 2012, 30 (15)
[7] FGFR1 Amplification in Squamous Cell Carcinoma of The Lung
Heist, Rebecca S.
Mino-Kenudson, Mari
Sequist, Lecia V.
Tammireddy, Swathi
Morrissey, Laura
Christiani, David C.
Engelman, Jeffrey A.
Iafrate, A. John
JOURNAL OF THORACIC ONCOLOGY, 2012, 7 (12) : 1775 - 1780
[8] Genomic insights into the mechanisms of FGFR1 dependency in squamous cell lung cancer
Makinen, Netta
Meyerson, Matthew
JOURNAL OF CLINICAL INVESTIGATION, 2023, 133 (21):
[9] FGFR1 gene amplification in small cell lung cancer
Park, Ji Soo
Lee, Jae-Seok
Shim, Hyo Sup
Kim, Hye Ryun
Lim, Sun Min
Kim, Joo Hang
Cho, Byoung Chul
CANCER RESEARCH, 2014, 74 (19)
[10] MYCxing It Up with FGFR1 in Squamous Cell Lung Cancer
Lockwood, William
Politi, Katerina
CANCER DISCOVERY, 2014, 4 (02) : 152 - 154

← 1 2 3 4 5 →