TY - JOUR
T1 - Theraputic targeting of Trk supresses tumor proliferation and enhances cisplatin activity in HNSCC
AU - Yilmaz, Turker
AU - Jiffar, Tilahun
AU - De La Garza, Gabriel
AU - Lin, Heather
AU - Milas, Zvonimir
AU - Takahashi, Yoko
AU - Hanna, Ehab
AU - MacIntyre, Terry
AU - Brown, Jeffrey L.
AU - Myers, Jeffrey N.
AU - Kupferman, Michael E.
PY - 2010/9/15
Y1 - 2010/9/15
N2 - 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 prooncogenic 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.
AB - 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 prooncogenic 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.
KW - AZ64
KW - Cisplatin resistance
KW - HNSCC
KW - Small molecule inhibitor
KW - Squamous cell carcinoma
KW - Therapeutic strategies
KW - TrkB
UR - http://www.scopus.com/inward/record.url?scp=77957131559&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77957131559&partnerID=8YFLogxK
U2 - 10.4161/cbt.10.6.12782
DO - 10.4161/cbt.10.6.12782
M3 - Article
C2 - 20703101
AN - SCOPUS:77957131559
SN - 1538-4047
VL - 10
SP - 644
EP - 653
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 6
ER -