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Molecular Pharmacology

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Research ArticleArticle

A Receptor Tyrosine Kinase Network Composed of Fibroblast Growth Factor Receptors, Epidermal Growth Factor Receptor, v-erb-b2 Erythroblastic Leukemia Viral Oncogene Homolog 2, and Hepatocyte Growth Factor Receptor Drives Growth and Survival of Head and Neck Squamous Carcinoma Cell Lines

Katherine R. Singleton, Jihye Kim, Trista K. Hinz, Lindsay A. Marek, Matias Casás-Selves, Clark Hatheway, Aik Choon Tan, James DeGregori and Lynn E. Heasley
Molecular Pharmacology April 2013, 83 (4) 882-893; DOI: https://doi.org/10.1124/mol.112.084111
Katherine R. Singleton
Departments of Craniofacial Biology (K.R.S., T.K.H., L.A.M., C.H., L.E.H.), Medicine (J.K., A.C.T.), and Biochemistry and Molecular Genetics (M.C.-S., J.D.), University of Colorado Anschutz Medical Campus, Aurora, Colorado
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Jihye Kim
Departments of Craniofacial Biology (K.R.S., T.K.H., L.A.M., C.H., L.E.H.), Medicine (J.K., A.C.T.), and Biochemistry and Molecular Genetics (M.C.-S., J.D.), University of Colorado Anschutz Medical Campus, Aurora, Colorado
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Trista K. Hinz
Departments of Craniofacial Biology (K.R.S., T.K.H., L.A.M., C.H., L.E.H.), Medicine (J.K., A.C.T.), and Biochemistry and Molecular Genetics (M.C.-S., J.D.), University of Colorado Anschutz Medical Campus, Aurora, Colorado
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Lindsay A. Marek
Departments of Craniofacial Biology (K.R.S., T.K.H., L.A.M., C.H., L.E.H.), Medicine (J.K., A.C.T.), and Biochemistry and Molecular Genetics (M.C.-S., J.D.), University of Colorado Anschutz Medical Campus, Aurora, Colorado
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Matias Casás-Selves
Departments of Craniofacial Biology (K.R.S., T.K.H., L.A.M., C.H., L.E.H.), Medicine (J.K., A.C.T.), and Biochemistry and Molecular Genetics (M.C.-S., J.D.), University of Colorado Anschutz Medical Campus, Aurora, Colorado
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Clark Hatheway
Departments of Craniofacial Biology (K.R.S., T.K.H., L.A.M., C.H., L.E.H.), Medicine (J.K., A.C.T.), and Biochemistry and Molecular Genetics (M.C.-S., J.D.), University of Colorado Anschutz Medical Campus, Aurora, Colorado
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Aik Choon Tan
Departments of Craniofacial Biology (K.R.S., T.K.H., L.A.M., C.H., L.E.H.), Medicine (J.K., A.C.T.), and Biochemistry and Molecular Genetics (M.C.-S., J.D.), University of Colorado Anschutz Medical Campus, Aurora, Colorado
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James DeGregori
Departments of Craniofacial Biology (K.R.S., T.K.H., L.A.M., C.H., L.E.H.), Medicine (J.K., A.C.T.), and Biochemistry and Molecular Genetics (M.C.-S., J.D.), University of Colorado Anschutz Medical Campus, Aurora, Colorado
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Lynn E. Heasley
Departments of Craniofacial Biology (K.R.S., T.K.H., L.A.M., C.H., L.E.H.), Medicine (J.K., A.C.T.), and Biochemistry and Molecular Genetics (M.C.-S., J.D.), University of Colorado Anschutz Medical Campus, Aurora, Colorado
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Abstract

Our laboratory has previously shown that some gefitinib-insensitive head and neck squamous cell carcinoma (HNSCC) cell lines exhibit dominant autocrine fibroblast growth factor receptor (FGFR) signaling. Herein, we deployed a whole-genome loss-of-function screen to identify genes whose knockdown potentiated the inhibitory effect of the FGFR inhibitor, AZ8010, in HNSCC cell lines. Three HNSCC cell lines expressing a genome-wide small hairpin RNA (shRNA) library were treated with AZ8010 and the abundance of shRNA sequences was assessed by deep sequencing. Under-represented shRNAs in treated cells are expected to target genes important for survival with AZ8010 treatment. Synthetic lethal hits were validated with specific inhibitors and independent shRNAs. We found that multiple alternate receptors provided protection from FGFR inhibition, including receptor tyrosine kinases (RTKs), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2), and hepatocyte growth factor receptor (MET). We showed that specific knockdown of either ERBB2 or MET in combination with FGFR inhibition led to increased inhibition of growth relative to FGFR tyrosine kinase inhibitor (TKI) treatment alone. These results were confirmed using specific small molecule inhibitors of either ERBB family members or MET. Moreover, the triple combination of FGFR, MET, and ERBB family inhibitors showed the largest inhibition of growth and induction of apoptosis compared with the double combinations. These results reveal a role for alternate RTKs in maintaining progrowth and survival signaling in HNSCC cells in the setting of FGFR inhibition. Thus, improved therapies for HNSCC patients could involve rationally designed combinations of TKIs targeting FGFR, ERBB family members, and MET.

Footnotes

  • This research was supported by the National Institutes of Health [Grant R01-CA127105].

  • dx.doi.org/10.1124/mol.112.084111.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Received November 28, 2012.
  • Accepted January 31, 2013.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (4)
Molecular Pharmacology
Vol. 83, Issue 4
1 Apr 2013
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A Receptor Tyrosine Kinase Network Composed of Fibroblast Growth Factor Receptors, Epidermal Growth Factor Receptor, v-erb-b2 Erythroblastic Leukemia Viral Oncogene Homolog 2, and Hepatocyte Growth Factor Receptor Drives Growth and Survival of Head and N…
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Research ArticleArticle

Synthetic Lethal Relations Identify a RTK Network in HNSCC

Katherine R. Singleton, Jihye Kim, Trista K. Hinz, Lindsay A. Marek, Matias Casás-Selves, Clark Hatheway, Aik Choon Tan, James DeGregori and Lynn E. Heasley
Molecular Pharmacology April 1, 2013, 83 (4) 882-893; DOI: https://doi.org/10.1124/mol.112.084111

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Research ArticleArticle

Synthetic Lethal Relations Identify a RTK Network in HNSCC

Katherine R. Singleton, Jihye Kim, Trista K. Hinz, Lindsay A. Marek, Matias Casás-Selves, Clark Hatheway, Aik Choon Tan, James DeGregori and Lynn E. Heasley
Molecular Pharmacology April 1, 2013, 83 (4) 882-893; DOI: https://doi.org/10.1124/mol.112.084111
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