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Updated: Jul 13, 2025
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
FAK Drives Resistance to Therapy in HPV-Negative Head and Neck Cancer in a p53-Dependent Manner
Phillip M Pifer1, Liangpeng Yang2, Manish Kumar3
1Department of Radiation Oncology, University of Pittsburgh, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.
Purpose:
Radiation and platinum-based chemotherapy form the backbone of therapy in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). We have correlated focal adhesion kinase (FAK/PTK2) expression with radioresistance and worse outcomes in these patients. However, the importance of FAK in driving radioresistance and its effects on chemoresistance in these patients remains unclear.
Experimental Design:
We performed an in vivo shRNA screen using targetable libraries to identify novel therapeutic sensitizers for radiation and chemotherapy.
Results:
We identified FAK as an excellent target for both radio- and chemosensitization. Because TP53 is mutated in over 80% of HPV-negative HNSCC, we hypothesized that mutant TP53 may facilitate FAK-mediated therapy resistance. FAK inhibitor increased sensitivity to radiation, increased DNA damage, and repressed homologous recombination and nonhomologous end joining repair in mutant, but not wild-type, TP53 HPV-negative HNSCC cell lines. The mutant TP53 cisplatin-resistant cell line had increased FAK phosphorylation compared with wild-type, and FAK inhibition partially reversed cisplatin resistance. To validate these findings, we utilized an HNSCC cohort to show that FAK copy number and gene expression were associated with worse disease-free survival in mutant TP53, but not wild-type TP53, HPV-negative HNSCC tumors.
Conclusions:
FAK may represent a targetable therapeutic sensitizer linked to a known genomic marker of resistance.
Insights
Focal adhesion kinase (FAK) inhibition sensitizes human papillomavirus-negative head and neck squamous cell carcinoma to radiation and chemotherapy, particularly in tumors with mutant TP53. This highlights FAK as a potential therapeutic target for improving treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Human papillomavirus-negative head and neck squamous cell carcinoma (HNSCC) is typically treated with radiation and platinum-based chemotherapy.
- Focal adhesion kinase (FAK/PTK2) expression is linked to radioresistance and poorer outcomes in HNSCC patients.
- The precise role of FAK in mediating radioresistance and chemoresistance in HPV-negative HNSCC remains to be fully elucidated.
Purpose of the Study:
- To identify novel therapeutic sensitizers for radiation and chemotherapy in HPV-negative HNSCC.
- To investigate the role of FAK in therapy resistance, particularly in the context of TP53 mutations.
Main Methods:
- An in vivo shRNA screen was employed using targetable libraries to discover new sensitizing agents.
- Experiments involved utilizing FAK inhibitors on HPV-negative HNSCC cell lines with mutant and wild-type TP53.
- Analysis of an HNSCC patient cohort was performed to correlate FAK copy number and gene expression with clinical outcomes.
Main Results:
- FAK was identified as a promising target for both radio- and chemosensitization.
- FAK inhibition enhanced sensitivity to radiation, increased DNA damage, and suppressed DNA repair pathways (homologous recombination and nonhomologous end joining) in TP53-mutant HNSCC cells.
- FAK inhibition partially reversed cisplatin resistance in TP53-mutant HNSCC cells, which exhibited higher FAK phosphorylation.
- In a patient cohort, elevated FAK copy number and gene expression correlated with worse disease-free survival in HPV-negative HNSCC with mutant TP53.
Conclusions:
- FAK inhibition demonstrates significant potential as a therapeutic sensitizer in HPV-negative HNSCC.
- Targeting FAK may be particularly effective in tumors harboring TP53 mutations, suggesting a link between FAK and TP53-mediated therapy resistance.
- FAK represents a druggable target that can be combined with genomic markers like TP53 status for personalized treatment strategies in HNSCC.
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