FAK Drives Resistance to Therapy in HPV-Negative Head and Neck Cancer in a p53-Dependent Manner
©2023 The Authors; Published by the American Association for Cancer Research..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
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| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 30(2024), 1 vom: 05. Jan., Seite 187-197 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Pifer, Phillip M [VerfasserIn] |
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| Links: |
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| Themen: |
Cisplatin |
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| Anmerkungen: |
Date Completed 08.01.2024 Date Revised 05.04.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1158/1078-0432.CCR-23-0964 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM363130314 |
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| 100 | 1 | |a Pifer, Phillip M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a FAK Drives Resistance to Therapy in HPV-Negative Head and Neck Cancer in a p53-Dependent Manner |
| 264 | 1 | |c 2024 | |
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| 500 | |a Date Completed 08.01.2024 | ||
| 500 | |a Date Revised 05.04.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2023 The Authors; Published by the American Association for Cancer Research. | ||
| 520 | |a 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 | ||
| 520 | |a EXPERIMENTAL DESIGN: We performed an in vivo shRNA screen using targetable libraries to identify novel therapeutic sensitizers for radiation and chemotherapy | ||
| 520 | |a 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 | ||
| 520 | |a CONCLUSIONS: FAK may represent a targetable therapeutic sensitizer linked to a known genomic marker of resistance | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 650 | 7 | |a Tumor Suppressor Protein p53 |2 NLM | |
| 700 | 1 | |a Yang, Liangpeng |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Manish |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Tongxin |e verfasserin |4 aut | |
| 700 | 1 | |a Frederick, Mitchell |e verfasserin |4 aut | |
| 700 | 1 | |a Hefner, Andrew |e verfasserin |4 aut | |
| 700 | 1 | |a Beadle, Beth |e verfasserin |4 aut | |
| 700 | 1 | |a Molkentine, David |e verfasserin |4 aut | |
| 700 | 1 | |a Molkentine, Jessica |e verfasserin |4 aut | |
| 700 | 1 | |a Dhawan, Annika |e verfasserin |4 aut | |
| 700 | 1 | |a Abdelhakiem, Mohamed |e verfasserin |4 aut | |
| 700 | 1 | |a Osman, Abdullah A |e verfasserin |4 aut | |
| 700 | 1 | |a Leibowitz, Brian J |e verfasserin |4 aut | |
| 700 | 1 | |a Myers, Jeffrey N |e verfasserin |4 aut | |
| 700 | 1 | |a Pickering, Curtis R |e verfasserin |4 aut | |
| 700 | 1 | |a Sandulache, Vlad C |e verfasserin |4 aut | |
| 700 | 1 | |a Heymach, John |e verfasserin |4 aut | |
| 700 | 1 | |a Skinner, Heath D |e verfasserin |4 aut | |
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