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Effect of selective small molecule inhibitors on MMP-9 and VEGFR-1 expression in p16-positive and -negative squamous
Benedikt Kramer1, Johannes David Schultz2, Clemens Hock1
1Department of Otorhinolaryngology Head and Neck Surgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Abstract:
The identification of molecular targets in the therapy of human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is a primary aim of cancer research. Matrix metalloproteinase 9 (MMP-9) and vascular endothelial growth factor receptor (VEGFR) have important roles in the development of HNSCC. The tyrosine kinase inhibitors, nilotinib, dasatinib, erlotinib and gefitinib are well established in the targeted therapy of tumors other than HNSCC. The present study aimed to investigate the alteration of MMP-9 and VEGFR-1 expression patterns following treatment with these tyrosine kinase inhibitors in p16-positive and -negative squamous carcinoma cells. MMP-9 and VEGFR-1 expression was evaluated using an ELISA in HNSCC 11A, HNSCC 14C and p16-positive CERV196 tumor cell lines, following treatment with nilotinib, dasatinib, erlotinib and gefitinib. A statistically significant reduction in MMP-9 and VEGFR-1 expression was observed in the p16-negative HNSCC 11A cells following treatment with all inhibitors (P<0.05). VEGFR-1 expression was significantly increased in p16-positive SCC cells following treatment with nilotinib, dasatinib, erlotinib and gefitinib (P<0.05). The expression of MMP-9 and VEGFR-1 was significantly altered by treatment with nilotinib, dasatinib, erlotinib and gefitinib in vitro. The results of the present study are attributed to the efficacy of the tested drugs and present potential compensatory strategies of cancer cells to avoid the antiangiogenic properties of the tested tyrosine kinase inhibitors in vitro.
Insights
Tyrosine kinase inhibitors reduced MMP-9 and VEGFR-1 in p16-negative HNSCC cells but increased VEGFR-1 in p16-positive cells, indicating potential cancer cell adaptation strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) requires novel molecular targets for therapy.
- Matrix metalloproteinase 9 (MMP-9) and vascular endothelial growth factor receptor (VEGFR) are implicated in HNSCC development.
- Tyrosine kinase inhibitors (TKIs) like nilotinib, dasatinib, erlotinib, and gefitinib are used in other cancers.
Purpose of the Study:
- To investigate the effects of specific TKIs on MMP-9 and VEGFR-1 expression in p16-positive and p16-negative HNSCC cell lines.
- To explore potential therapeutic strategies targeting molecular pathways in HPV-associated HNSCC.
Main Methods:
- Utilized ELISA to quantify MMP-9 and VEGFR-1 expression in HNSCC cell lines (11A, 14C, CERV196) after treatment with nilotinib, dasatinib, erlotinib, and gefitinib.
- Compared expression patterns between p16-positive and p16-negative HNSCC cell lines.
Main Results:
- A significant decrease in MMP-9 and VEGFR-1 was observed in p16-negative HNSCC 11A cells across all tested TKIs (P<0.05).
- Conversely, VEGFR-1 expression significantly increased in p16-positive SCC cells following TKI treatment (P<0.05).
- The study demonstrated significant alterations in MMP-9 and VEGFR-1 expression in vitro.
Conclusions:
- The tested TKIs significantly alter MMP-9 and VEGFR-1 expression in HNSCC cell lines.
- Observed increases in VEGFR-1 in p16-positive cells may represent compensatory mechanisms against TKI antiangiogenic effects.
- These findings suggest complex cellular responses to targeted therapies in HNSCC.
