TY - JOUR
T1 - FAK Drives Resistance to Therapy in HPV-Negative Head and Neck Cancer in a p53-Dependent Manner
AU - Pifer, Phillip M.
AU - Yang, Liangpeng
AU - Kumar, Manish
AU - Xie, Tongxin
AU - Frederick, Mitchell J
AU - Hefner, Andrew
AU - Beadle, Beth
AU - Molkentine, David
AU - Molkentine, Jessica
AU - Dhawan, Annika
AU - Abdelhakiem, Mohamed
AU - Osman, Abdullah A.
AU - Leibowitz, Brian J.
AU - Myers, Jeffrey N.
AU - Pickering, Curtis R.
AU - Sandulache, Vlad C.
AU - Heymach, John
AU - Skinner, Heath
N1 - Publisher Copyright:
©2023 The Authors; Published by the American Association for Cancer Research.
PY - 2024/1/10
Y1 - 2024/1/10
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-23-0964
DO - 10.1158/1078-0432.CCR-23-0964
M3 - Article
C2 - 37819945
AN - SCOPUS:85181760833
SN - 1078-0432
VL - 30
SP - 187
EP - 197
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -