Abstract

Radiation and platinum-based chemotherapy form the backbone of therapy in HPV-negative head and neck squamous cell carcinoma (HNSCC). We have correlated focal adhesion kinase (FAK/PTK2) expression with radioresistance and worse outcome in these patients. However, the importance of FAK in driving radioresistance and its effects on chemoresistance in these patients remain unclear.We performed an in vivo shRNA screen using targetable libraries to identify novel therapeutic sensitizers for radiation and chemotherapy.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 non-homologous end joining repair in mutant, but not wild-type, TP53 HPV-negative HNSCC cell lines. Mutant TP53 cisplatin-resistant cell line had increased FAK phosphorylation compared to wild-type, and FAK inhibition partially reversed cisplatin resistance. To validate these findings, we utilized a 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.FAK may represent a targetable therapeutic sensitizer linked to a known genomic marker of resistance.

View details for DOI 10.1158/1078-0432.CCR-23-0964

View details for PubMedID 37819945