An inducible TGF-β2-TGFβR pathway modulates the sensitivity of HNSCC cells to tyrosine kinase inhibitors targeting dominant receptor tyrosine kinases

Emily K. Kleczko, Jihye Kim, Stephen B. Keysar, Lydia R. Heasley, Justin R. Eagles, Matthew Simon, Marianne E. Marshall, Katherine R. Singleton, Antonio Jimeno, Aik-Choon Tan, Lynn E. Heasley

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The epidermal growth factor receptor (EGFR) is overexpressed in approximately 90% of head and neck squamous cell carcinomas (HNSCC), and molecularly targeted therapy against the EGFR with the monoclonal antibody cetuximab modestly increases overall survival in head and neck cancer patients. We hypothesize that co-signaling through additional pathways limits the efficacy of cetuximab and EGFR-specific tyrosine kinase inhibitors (TKIs) in the clinical treatment of HNSCC. Analysis of gene expression changes in HNSCC cell lines treated 4 days with TKIs targeting EGFR and/or fibroblast growth factor receptors (FGFRs) identified transforming growth factor beta 2 (TGF-β2) induction in the three cell lines tested. Measurement of TGF-β2 mRNA validated this observation and extended it to additional cell lines. Moreover, TGF-β2 mRNA was increased in primary patient HNSCC xenografts treated for 4 weeks with cetuximab, demonstrating in vivo relevance of these findings. Functional genomics analyses with shRNA libraries identified TGF-β2 and TGF-β receptors (TGFβRs) as synthetic lethal genes in the context of TKI treatment. Further, direct RNAi-mediated silencing of TGF-β2 inhibited cell growth, both alone and in combination with TKIs. Also, a pharmacological TGFβRI inhibitor similarly inhibited basal growth and enhanced TKI efficacy. In summary, the studies support a TGF-β2-TGFβR pathway as a TKI-inducible growth pathway in HNSCC that limits efficacy of EGFR-specific inhibitors.

Original languageEnglish
Article numbere0123600
JournalPLoS One
Volume10
Issue number5
DOIs
Publication statusPublished - 2015 May 6
Externally publishedYes

Fingerprint

transforming growth factor beta 2
squamous cell carcinoma
Receptor Protein-Tyrosine Kinases
Transforming Growth Factor beta
Protein-Tyrosine Kinases
neck
tyrosine
Epidermal Growth Factor Receptor
phosphotransferases (kinases)
receptors
Cells
cell lines
cells
Cell Line
Lethal Genes
Synthetic Genes
synthetic genes
Fibroblast Growth Factor Receptors
Growth Inhibitors
Messenger RNA

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

An inducible TGF-β2-TGFβR pathway modulates the sensitivity of HNSCC cells to tyrosine kinase inhibitors targeting dominant receptor tyrosine kinases. / Kleczko, Emily K.; Kim, Jihye; Keysar, Stephen B.; Heasley, Lydia R.; Eagles, Justin R.; Simon, Matthew; Marshall, Marianne E.; Singleton, Katherine R.; Jimeno, Antonio; Tan, Aik-Choon; Heasley, Lynn E.

In: PLoS One, Vol. 10, No. 5, e0123600, 06.05.2015.

Research output: Contribution to journalArticle

Kleczko, EK, Kim, J, Keysar, SB, Heasley, LR, Eagles, JR, Simon, M, Marshall, ME, Singleton, KR, Jimeno, A, Tan, A-C & Heasley, LE 2015, 'An inducible TGF-β2-TGFβR pathway modulates the sensitivity of HNSCC cells to tyrosine kinase inhibitors targeting dominant receptor tyrosine kinases', PLoS One, vol. 10, no. 5, e0123600. https://doi.org/10.1371/journal.pone.0123600
Kleczko, Emily K. ; Kim, Jihye ; Keysar, Stephen B. ; Heasley, Lydia R. ; Eagles, Justin R. ; Simon, Matthew ; Marshall, Marianne E. ; Singleton, Katherine R. ; Jimeno, Antonio ; Tan, Aik-Choon ; Heasley, Lynn E. / An inducible TGF-β2-TGFβR pathway modulates the sensitivity of HNSCC cells to tyrosine kinase inhibitors targeting dominant receptor tyrosine kinases. In: PLoS One. 2015 ; Vol. 10, No. 5.
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