title: An Inducible TGF-β2-TGFβR Pathway Modulates the Sensitivity of HNSCC Cells to Tyrosine Kinase Inhibitors Targeting Dominant Receptor Tyrosine Kinases.
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.
authors.affiliation: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Kleczko
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Keysar
authors.affiliation: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Lydia R
authors.initials: LR
authors.lastname: Heasley
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Eagles
authors.affiliation: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Simon
authors.affiliation: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Marianne E
authors.initials: ME
authors.lastname: Marshall
authors.affiliation: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Singleton
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Aik-Choon
authors.initials: AC
authors.lastname: Tan
authors.affiliation: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America; Veterans Affairs Eastern Colorado Healthcare System, Denver, Colorado, United States of America.
authors.forename: Lynn E
authors.initials: LE
authors.lastname: Heasley
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000068818:Cetuximab / Q000494:pharmacology*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D000068818:Cetuximab