Theraputic targeting of Trk supresses tumor proliferation and enhances cisplatin activity in HNSCC.
Head and neck squamous cell carcinoma (HNSCC) is a biologically aggressive disease that has been modestly impacted by improvements in therapeutic strategies. Several lines of evidence support the role of TrkB for invasion and metastasis in various solid tumor models, and we have shown an important function of this receptor in HNSCC tumor biology. Therapeutic modulation of TrkB function has been supported in the literature by the development of small molecule inhibitors (SMI) with minimal success. To assess the validity of targeting TrkB in HNSCC, we tested a novel agent, AZ64 and show significant dose and time-dependent inhibition of cellular proliferation in cell lines. Genetic studies revealed the specificity of this compound for the TrkB receptor, as exposure of cells that had genetic suppression of TrkB did not demonstrate abrogated oncogenic signaling. We next assessed the impact of AZ64 as a chemotherapy-sensitizer and identified an enhancement of cisplatin-mediated anti-proliferation across all cell lines. We then demonstrated that AZ64 can overcome chemotherapy resistance in a novel model of cisplatin resistance in HNSCC. Modulation of the pro-oncogenic STAT3 and Src pathways was identified, suggesting molecular mechanisms of action for AZ64. In this study, we demonstrate the feasibility of targeting TrkB and suggest a novel approach for the treatment of some chemotherapy-resistant HNSCC.
Yilmaz
Turker
T
Department of Head & Neck Surgery, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.
Jiffar
Tilahun
T
de la Garza
Gabriel
G
Lin
Heather
H
Milas
Zvonimir
Z
Takahashi
Yoko
Y
Hanna
Ehab
E
MacIntyre
Terry
T
Brown
Jeffrey L
JL
Myers
Jeffrey N
JN
Kupferman
Michael E
ME
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005240:Feasibility Studies; D057809:HEK293 Cells; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D051379:Mice; D041681:NIH 3T3 Cells; D034622:RNA Interference; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019061:src-Family Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; D020813:Receptor, trkB; D019061:src-Family Kinases; D002945:Cisplatin