Truncated FGFR2 is a clinically actionable oncogene in multiple cancers

Daniel Zingg; Jinhyuk Bhin; Julia Yemelyanenko; Sjors M. Kas; Frank Rolfs; Catrin Lutz; Jessica K. Lee; Sjoerd Klarenbeek; Ian M. Silverman; Stefano Annunziato; Chang S. Chan; Sander R. Piersma; Timo Eijkman; Madelon Badoux; Ewa Gogola; Bjørn Siteur; Justin Sprengers; Bim de Klein; Richard R. de Goeij-de Haas; Gregory M. Riedlinger; Hua Ke; Russell Madison; Anne Paulien Drenth; Eline van der Burg; Eva Schut; Linda Henneman; Martine H. van Miltenburg; Natalie Proost; Huiling Zhen; Ellen Wientjens; Roebi de Bruijn; Julian R. de Ruiter; Ute Boon; Renske de Korte-Grimmerink; Bastiaan van Gerwen; Luis Féliz; Ghassan K. Abou-Alfa; Jeffrey S. Ross; Marieke van de Ven; Sven Rottenberg; Edwin Cuppen; Anne Vaslin Chessex; Siraj M. Ali; Timothy C. Burn; Connie R. Jimenez; Shridar Ganesan; Lodewyk F.A. Wessels; Jos Jonkers

doi:10.1038/s41586-022-05066-5

Truncated FGFR2 is a clinically actionable oncogene in multiple cancers

Daniel Zingg, Jinhyuk Bhin, Julia Yemelyanenko, Sjors M. Kas, Frank Rolfs, Catrin Lutz, Jessica K. Lee, Sjoerd Klarenbeek, Ian M. Silverman, Stefano Annunziato, Chang S. Chan, Sander R. Piersma, Timo Eijkman, Madelon Badoux, Ewa Gogola, Bjørn Siteur, Justin Sprengers, Bim de Klein, Richard R. de Goeij-de Haas, Gregory M. RiedlingerHua Ke, Russell Madison, Anne Paulien Drenth, Eline van der Burg, Eva Schut, Linda Henneman, Martine H. van Miltenburg, Natalie Proost, Huiling Zhen, Ellen Wientjens, Roebi de Bruijn, Julian R. de Ruiter, Ute Boon, Renske de Korte-Grimmerink, Bastiaan van Gerwen, Luis Féliz, Ghassan K. Abou-Alfa, Jeffrey S. Ross, Marieke van de Ven, Sven Rottenberg, Edwin Cuppen, Anne Vaslin Chessex, Siraj M. Ali, Timothy C. Burn, Connie R. Jimenez, Shridar Ganesan, Lodewyk F.A. Wessels, Jos Jonkers

Rutgers, The State University

Research output: Contribution to journal › Article › peer-review

Abstract

Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer¹. However, clinical responses to FGFR inhibitors have remained variable^1–9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening^10,11 and tumour modelling in mice^12,13, and find that the truncation of exon 18 (E18) of Fgfr2 is a potent driver mutation. Human oncogenomic datasets revealed a diverse set of FGFR2 alterations, including rearrangements, E1–E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing the transcription of E18-truncated FGFR2 (FGFR2^ΔE18). Functional in vitro and in vivo examination of a compendium of FGFR2^ΔE18 and full-length variants pinpointed FGFR2-E18 truncation as single-driver alteration in cancer. By contrast, the oncogenic competence of FGFR2 full-length amplifications depended on a distinct landscape of cooperating driver genes. This suggests that genomic alterations that generate stable FGFR2^ΔE18 variants are actionable therapeutic targets, which we confirmed in preclinical mouse and human tumour models, and in a clinical trial. We propose that cancers containing any FGFR2 variant with a truncated E18 should be considered for FGFR-targeted therapies.

Original language	American English
Pages (from-to)	609-617
Number of pages	9
Journal	Nature
Volume	608
Issue number	7923
DOIs	https://doi.org/10.1038/s41586-022-05066-5
State	Published - Aug 18 2022

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Zingg, D., Bhin, J., Yemelyanenko, J., Kas, S. M., Rolfs, F., Lutz, C., Lee, J. K., Klarenbeek, S., Silverman, I. M., Annunziato, S., Chan, C. S., Piersma, S. R., Eijkman, T., Badoux, M., Gogola, E., Siteur, B., Sprengers, J., de Klein, B., de Goeij-de Haas, R. R., ... Jonkers, J. (2022). Truncated FGFR2 is a clinically actionable oncogene in multiple cancers. Nature, 608(7923), 609-617. https://doi.org/10.1038/s41586-022-05066-5

@article{41b48ef7acda472d866ab822d9e2772e,

title = "Truncated FGFR2 is a clinically actionable oncogene in multiple cancers",

abstract = "Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer1. However, clinical responses to FGFR inhibitors have remained variable1–9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening10,11 and tumour modelling in mice12,13, and find that the truncation of exon 18 (E18) of Fgfr2 is a potent driver mutation. Human oncogenomic datasets revealed a diverse set of FGFR2 alterations, including rearrangements, E1–E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing the transcription of E18-truncated FGFR2 (FGFR2ΔE18). Functional in vitro and in vivo examination of a compendium of FGFR2ΔE18 and full-length variants pinpointed FGFR2-E18 truncation as single-driver alteration in cancer. By contrast, the oncogenic competence of FGFR2 full-length amplifications depended on a distinct landscape of cooperating driver genes. This suggests that genomic alterations that generate stable FGFR2ΔE18 variants are actionable therapeutic targets, which we confirmed in preclinical mouse and human tumour models, and in a clinical trial. We propose that cancers containing any FGFR2 variant with a truncated E18 should be considered for FGFR-targeted therapies.",

author = "Daniel Zingg and Jinhyuk Bhin and Julia Yemelyanenko and Kas, {Sjors M.} and Frank Rolfs and Catrin Lutz and Lee, {Jessica K.} and Sjoerd Klarenbeek and Silverman, {Ian M.} and Stefano Annunziato and Chan, {Chang S.} and Piersma, {Sander R.} and Timo Eijkman and Madelon Badoux and Ewa Gogola and Bj{\o}rn Siteur and Justin Sprengers and {de Klein}, Bim and {de Goeij-de Haas}, {Richard R.} and Riedlinger, {Gregory M.} and Hua Ke and Russell Madison and Drenth, {Anne Paulien} and {van der Burg}, Eline and Eva Schut and Linda Henneman and {van Miltenburg}, {Martine H.} and Natalie Proost and Huiling Zhen and Ellen Wientjens and {de Bruijn}, Roebi and {de Ruiter}, {Julian R.} and Ute Boon and {de Korte-Grimmerink}, Renske and {van Gerwen}, Bastiaan and Luis F{\'e}liz and Abou-Alfa, {Ghassan K.} and Ross, {Jeffrey S.} and {van de Ven}, Marieke and Sven Rottenberg and Edwin Cuppen and Chessex, {Anne Vaslin} and Ali, {Siraj M.} and Burn, {Timothy C.} and Jimenez, {Connie R.} and Shridar Ganesan and Wessels, {Lodewyk F.A.} and Jos Jonkers",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2022",

month = aug,

day = "18",

doi = "10.1038/s41586-022-05066-5",

language = "American English",

volume = "608",

pages = "609--617",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7923",

}

Zingg, D, Bhin, J, Yemelyanenko, J, Kas, SM, Rolfs, F, Lutz, C, Lee, JK, Klarenbeek, S, Silverman, IM, Annunziato, S, Chan, CS, Piersma, SR, Eijkman, T, Badoux, M, Gogola, E, Siteur, B, Sprengers, J, de Klein, B, de Goeij-de Haas, RR, Riedlinger, GM, Ke, H, Madison, R, Drenth, AP, van der Burg, E, Schut, E, Henneman, L, van Miltenburg, MH, Proost, N, Zhen, H, Wientjens, E, de Bruijn, R, de Ruiter, JR, Boon, U, de Korte-Grimmerink, R, van Gerwen, B, Féliz, L, Abou-Alfa, GK, Ross, JS, van de Ven, M, Rottenberg, S, Cuppen, E, Chessex, AV, Ali, SM, Burn, TC, Jimenez, CR, Ganesan, S, Wessels, LFA & Jonkers, J 2022, 'Truncated FGFR2 is a clinically actionable oncogene in multiple cancers', Nature, vol. 608, no. 7923, pp. 609-617. https://doi.org/10.1038/s41586-022-05066-5

TY - JOUR

T1 - Truncated FGFR2 is a clinically actionable oncogene in multiple cancers

AU - Zingg, Daniel

AU - Bhin, Jinhyuk

AU - Yemelyanenko, Julia

AU - Kas, Sjors M.

AU - Rolfs, Frank

AU - Lutz, Catrin

AU - Lee, Jessica K.

AU - Klarenbeek, Sjoerd

AU - Silverman, Ian M.

AU - Annunziato, Stefano

AU - Chan, Chang S.

AU - Piersma, Sander R.

AU - Eijkman, Timo

AU - Badoux, Madelon

AU - Gogola, Ewa

AU - Siteur, Bjørn

AU - Sprengers, Justin

AU - de Klein, Bim

AU - de Goeij-de Haas, Richard R.

AU - Riedlinger, Gregory M.

AU - Ke, Hua

AU - Madison, Russell

AU - Drenth, Anne Paulien

AU - van der Burg, Eline

AU - Schut, Eva

AU - Henneman, Linda

AU - van Miltenburg, Martine H.

AU - Proost, Natalie

AU - Zhen, Huiling

AU - Wientjens, Ellen

AU - de Bruijn, Roebi

AU - de Ruiter, Julian R.

AU - Boon, Ute

AU - de Korte-Grimmerink, Renske

AU - van Gerwen, Bastiaan

AU - Féliz, Luis

AU - Abou-Alfa, Ghassan K.

AU - Ross, Jeffrey S.

AU - van de Ven, Marieke

AU - Rottenberg, Sven

AU - Cuppen, Edwin

AU - Chessex, Anne Vaslin

AU - Ali, Siraj M.

AU - Burn, Timothy C.

AU - Jimenez, Connie R.

AU - Ganesan, Shridar

AU - Wessels, Lodewyk F.A.

AU - Jonkers, Jos

PY - 2022/8/18

Y1 - 2022/8/18

N2 - Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer1. However, clinical responses to FGFR inhibitors have remained variable1–9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening10,11 and tumour modelling in mice12,13, and find that the truncation of exon 18 (E18) of Fgfr2 is a potent driver mutation. Human oncogenomic datasets revealed a diverse set of FGFR2 alterations, including rearrangements, E1–E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing the transcription of E18-truncated FGFR2 (FGFR2ΔE18). Functional in vitro and in vivo examination of a compendium of FGFR2ΔE18 and full-length variants pinpointed FGFR2-E18 truncation as single-driver alteration in cancer. By contrast, the oncogenic competence of FGFR2 full-length amplifications depended on a distinct landscape of cooperating driver genes. This suggests that genomic alterations that generate stable FGFR2ΔE18 variants are actionable therapeutic targets, which we confirmed in preclinical mouse and human tumour models, and in a clinical trial. We propose that cancers containing any FGFR2 variant with a truncated E18 should be considered for FGFR-targeted therapies.

AB - Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer1. However, clinical responses to FGFR inhibitors have remained variable1–9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening10,11 and tumour modelling in mice12,13, and find that the truncation of exon 18 (E18) of Fgfr2 is a potent driver mutation. Human oncogenomic datasets revealed a diverse set of FGFR2 alterations, including rearrangements, E1–E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing the transcription of E18-truncated FGFR2 (FGFR2ΔE18). Functional in vitro and in vivo examination of a compendium of FGFR2ΔE18 and full-length variants pinpointed FGFR2-E18 truncation as single-driver alteration in cancer. By contrast, the oncogenic competence of FGFR2 full-length amplifications depended on a distinct landscape of cooperating driver genes. This suggests that genomic alterations that generate stable FGFR2ΔE18 variants are actionable therapeutic targets, which we confirmed in preclinical mouse and human tumour models, and in a clinical trial. We propose that cancers containing any FGFR2 variant with a truncated E18 should be considered for FGFR-targeted therapies.

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UR - http://www.scopus.com/inward/citedby.url?scp=85136216088&partnerID=8YFLogxK

U2 - 10.1038/s41586-022-05066-5

DO - 10.1038/s41586-022-05066-5

M3 - Article

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SN - 0028-0836

VL - 608

SP - 609

EP - 617

JO - Nature

JF - Nature

IS - 7923

ER -

Truncated FGFR2 is a clinically actionable oncogene in multiple cancers

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