Data from FAK Drives Resistance to Therapy in HPV-Negative Head and Neck Cancer in a p53-Dependent Manner

Abstract

<div>AbstractPurpose:<p>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/<i>PTK2</i>) 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.</p>Experimental Design:<p>We performed an <i>in vivo</i> shRNA screen using targetable libraries to identify novel therapeutic sensitizers for radiation and chemotherapy.</p>Results:<p>We identified FAK as an excellent target for both radio- and chemosensitization. Because <i>TP53</i> is mutated in over 80% of HPV-negative HNSCC, we hypothesized that mutant <i>TP53</i> 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, <i>TP53</i> HPV-negative HNSCC cell lines. The mutant <i>TP53</i> 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 <i>TP53</i>, but not wild-type <i>TP53</i>, HPV-negative HNSCC tumors.</p>Conclusions:<p>FAK may represent a targetable therapeutic sensitizer linked to a known genomic marker of resistance.</p></div>