RT Journal Article
SR Electronic
T1 FAK drives resistance to therapy in HPV-negative head and neck cancer in a p53-dependent manner
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.03.494547
DO 10.1101/2022.06.03.494547
A1 Phillip M. Pifer
A1 Liangpeng Yang
A1 Manish Kumar
A1 Tongxin Xie
A1 Mitchell Frederick
A1 Andrew Hefner
A1 Beth Beadle
A1 David Molkentine
A1 Jessica Molkentine
A1 Annika Dhawan
A1 Mohamed Abdelhakiem
A1 Abdullah A. Osman
A1 Jeffrey N. Myers
A1 Curtis R. Pickering
A1 Vlad C. Sandulache
A1 John Heymach
A1 Heath D. Skinner
YR 2022
UL http://biorxiv.org/content/early/2022/06/03/2022.06.03.494547.abstract
AB 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 address these questions and 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. Thus, FAK may represent a targetable therapeutic sensitizer linked to a known genomic marker of resistance.Competing Interest StatementThe authors have declared no competing interest.