Identification of a Therapeutic Strategy Targeting Amplified FGF19 in Liver Cancer by Oncogenomic Screening

Eric T. Sawey; Maia Chanrion; Chunlin Cai; Guanming Wu; Jianping Zhang; Lars Zender; Alice Zhao; Ronald W. Busuttil; Herman Yee; Lincoln Stein; Dorothy M. French; Richard S. Finn; Scott W. Lowe; Scott Powers

doi:10.1016/j.ccr.2011.01.040

Identification of a Therapeutic Strategy Targeting Amplified FGF19 in Liver Cancer by Oncogenomic Screening

Eric T. Sawey, Maia Chanrion, Chunlin Cai, Guanming Wu, Jianping Zhang, Lars Zender, Alice Zhao, Ronald W. Busuttil, Herman Yee, Lincoln Stein, Dorothy M. French, Richard S. Finn, Scott W. Lowe, Scott Powers

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348 Scopus citations

Abstract

We screened 124 genes that are amplified in human hepatocellular carcinoma (HCC) using a mouse hepatoblast model and identified 18 tumor-promoting genes, including CCND1 and its neighbor on 11q13.3, FGF19. Although it is widely assumed that CCND1 is the main driving oncogene of this common amplicon (15% frequency in HCC), both forward-transformation assays and RNAi-mediated inhibition in human HCC cells established that FGF19 is an equally important driver gene in HCC. Furthermore, clonal growth and tumorigenicity of HCC cells harboring the 11q13.3 amplicon were selectively inhibited by RNAi-mediated knockdown of CCND1 or FGF19, as well as by an anti-FGF19 antibody. These results show that 11q13.3 amplification could be an effective biomarker for patients most likely to respond to anti-FGF19 therapy.

Original language	English (US)
Pages (from-to)	347-358
Number of pages	12
Journal	Cancer Cell
Volume	19
Issue number	3
DOIs	https://doi.org/10.1016/j.ccr.2011.01.040
State	Published - Mar 8 2011
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccr.2011.01.040

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@article{44020ec24e814cae8878afb5c82f8c2e,

title = "Identification of a Therapeutic Strategy Targeting Amplified FGF19 in Liver Cancer by Oncogenomic Screening",

abstract = "We screened 124 genes that are amplified in human hepatocellular carcinoma (HCC) using a mouse hepatoblast model and identified 18 tumor-promoting genes, including CCND1 and its neighbor on 11q13.3, FGF19. Although it is widely assumed that CCND1 is the main driving oncogene of this common amplicon (15% frequency in HCC), both forward-transformation assays and RNAi-mediated inhibition in human HCC cells established that FGF19 is an equally important driver gene in HCC. Furthermore, clonal growth and tumorigenicity of HCC cells harboring the 11q13.3 amplicon were selectively inhibited by RNAi-mediated knockdown of CCND1 or FGF19, as well as by an anti-FGF19 antibody. These results show that 11q13.3 amplification could be an effective biomarker for patients most likely to respond to anti-FGF19 therapy.",

author = "Sawey, {Eric T.} and Maia Chanrion and Chunlin Cai and Guanming Wu and Jianping Zhang and Lars Zender and Alice Zhao and Busuttil, {Ronald W.} and Herman Yee and Lincoln Stein and French, {Dorothy M.} and Finn, {Richard S.} and Lowe, {Scott W.} and Scott Powers",

note = "Funding Information: We thank L. Bianco, J. Marchica, T. Wang, A. Bakleh, and Q. Liu for technical support, J. Duffy for his help preparing figures, and A. Ashkenazi for discussions. This work was supported by the Hope Funds for Cancer Research (E.T.S.), and NIH grants CA124648 (S.P.), CA105388 (S.P. and S.W.L.), and CA076905 (R.S.F.). S.W.L. is a Howard Hughes Investigator. R.S.F. is a recipient of an NIH-LRP award. E.T.S., S.P., and S.W.L. are members of the CSHL Cancer Target Discovery and Development Center (CTD 2 , supported by CA148532) and part of the NCI CTD 2 Network. ",

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doi = "10.1016/j.ccr.2011.01.040",

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T1 - Identification of a Therapeutic Strategy Targeting Amplified FGF19 in Liver Cancer by Oncogenomic Screening

AU - Sawey, Eric T.

AU - Chanrion, Maia

AU - Cai, Chunlin

AU - Wu, Guanming

AU - Zhang, Jianping

AU - Zender, Lars

AU - Zhao, Alice

AU - Busuttil, Ronald W.

AU - Yee, Herman

AU - Stein, Lincoln

AU - French, Dorothy M.

AU - Finn, Richard S.

AU - Lowe, Scott W.

AU - Powers, Scott

N1 - Funding Information: We thank L. Bianco, J. Marchica, T. Wang, A. Bakleh, and Q. Liu for technical support, J. Duffy for his help preparing figures, and A. Ashkenazi for discussions. This work was supported by the Hope Funds for Cancer Research (E.T.S.), and NIH grants CA124648 (S.P.), CA105388 (S.P. and S.W.L.), and CA076905 (R.S.F.). S.W.L. is a Howard Hughes Investigator. R.S.F. is a recipient of an NIH-LRP award. E.T.S., S.P., and S.W.L. are members of the CSHL Cancer Target Discovery and Development Center (CTD 2 , supported by CA148532) and part of the NCI CTD 2 Network.

PY - 2011/3/8

Y1 - 2011/3/8

N2 - We screened 124 genes that are amplified in human hepatocellular carcinoma (HCC) using a mouse hepatoblast model and identified 18 tumor-promoting genes, including CCND1 and its neighbor on 11q13.3, FGF19. Although it is widely assumed that CCND1 is the main driving oncogene of this common amplicon (15% frequency in HCC), both forward-transformation assays and RNAi-mediated inhibition in human HCC cells established that FGF19 is an equally important driver gene in HCC. Furthermore, clonal growth and tumorigenicity of HCC cells harboring the 11q13.3 amplicon were selectively inhibited by RNAi-mediated knockdown of CCND1 or FGF19, as well as by an anti-FGF19 antibody. These results show that 11q13.3 amplification could be an effective biomarker for patients most likely to respond to anti-FGF19 therapy.

AB - We screened 124 genes that are amplified in human hepatocellular carcinoma (HCC) using a mouse hepatoblast model and identified 18 tumor-promoting genes, including CCND1 and its neighbor on 11q13.3, FGF19. Although it is widely assumed that CCND1 is the main driving oncogene of this common amplicon (15% frequency in HCC), both forward-transformation assays and RNAi-mediated inhibition in human HCC cells established that FGF19 is an equally important driver gene in HCC. Furthermore, clonal growth and tumorigenicity of HCC cells harboring the 11q13.3 amplicon were selectively inhibited by RNAi-mediated knockdown of CCND1 or FGF19, as well as by an anti-FGF19 antibody. These results show that 11q13.3 amplification could be an effective biomarker for patients most likely to respond to anti-FGF19 therapy.

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Identification of a Therapeutic Strategy Targeting Amplified FGF19 in Liver Cancer by Oncogenomic Screening

Abstract

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