18F-FDG PET as an imaging biomarker for the response to FGFR-targeted therapy of cancer cells via FGFR-initiated mTOR/HK2 axis
© The author(s)..
Rationale: The overall clinical response to FGFR inhibitor (FGFRi) is far from satisfactory in cancer patients stratified by FGFR aberration, the current biomarker in clinical practice. A novel biomarker to evaluate the therapeutic response to FGFRi in a non-invasive and dynamic manner is thus greatly desired. Methods: Six FGFR-aberrant cancer cell lines were used, including four FGFRi-sensitive ones (NCI-H1581, NCI-H716, RT112 and Hep3B) and two FGFRi-resistant ones (primary for NCI-H2444 and acquired for NCI-H1581/AR). Cell viability and tumor xenograft growth analyses were performed to evaluate FGFRi sensitivities, accompanied by corresponding 18F-fluorodeoxyglucose (18F-FDG) uptake assay. mTOR/PLCγ/MEK-ERK signaling blockade by specific inhibitors or siRNAs was applied to determine the regulation mechanism. Results: FGFR inhibition decreased the in vitro accumulation of 18F-FDG only in four FGFRi-sensitive cell lines, but in neither of FGFRi-resistant ones. We then demonstrated that FGFRi-induced transcriptional downregulation of hexokinase 2 (HK2), a key factor of glucose metabolism and FDG trapping, via mTOR pathway leading to this decrease. Moreover, 18F-FDG PET imaging successfully differentiated the FGFRi-sensitive tumor xenografts from primary or acquired resistant ones by the tumor 18F-FDG accumulation change upon FGFRi treatment. Of note, both 18F-FDG tumor accumulation and HK2 expression could respond the administration/withdrawal of FGFRi in NCI-H1581 xenografts correspondingly. Conclusion: The novel association between the molecular mechanism (FGFR/mTOR/HK2 axis) and radiological phenotype (18F-FDG PET uptake) of FGFR-targeted therapy was demonstrated in multiple preclinical models. The adoption of 18F-FDG PET biomarker-based imaging strategy to assess response/resistance to FGFR inhibition may benefit treatment selection for cancer patients.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Theranostics - 12(2022), 14 vom: 01., Seite 6395-6408 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jiang, Yuchen [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 29.09.2022 Date Revised 18.10.2022 published: Electronic-eCollection Citation Status MEDLINE |
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| doi: |
10.7150/thno.74848 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM346842247 |
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| 100 | 1 | |a Jiang, Yuchen |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a 18F-FDG PET as an imaging biomarker for the response to FGFR-targeted therapy of cancer cells via FGFR-initiated mTOR/HK2 axis |
| 264 | 1 | |c 2022 | |
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| 500 | |a Date Completed 29.09.2022 | ||
| 500 | |a Date Revised 18.10.2022 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The author(s). | ||
| 520 | |a Rationale: The overall clinical response to FGFR inhibitor (FGFRi) is far from satisfactory in cancer patients stratified by FGFR aberration, the current biomarker in clinical practice. A novel biomarker to evaluate the therapeutic response to FGFRi in a non-invasive and dynamic manner is thus greatly desired. Methods: Six FGFR-aberrant cancer cell lines were used, including four FGFRi-sensitive ones (NCI-H1581, NCI-H716, RT112 and Hep3B) and two FGFRi-resistant ones (primary for NCI-H2444 and acquired for NCI-H1581/AR). Cell viability and tumor xenograft growth analyses were performed to evaluate FGFRi sensitivities, accompanied by corresponding 18F-fluorodeoxyglucose (18F-FDG) uptake assay. mTOR/PLCγ/MEK-ERK signaling blockade by specific inhibitors or siRNAs was applied to determine the regulation mechanism. Results: FGFR inhibition decreased the in vitro accumulation of 18F-FDG only in four FGFRi-sensitive cell lines, but in neither of FGFRi-resistant ones. We then demonstrated that FGFRi-induced transcriptional downregulation of hexokinase 2 (HK2), a key factor of glucose metabolism and FDG trapping, via mTOR pathway leading to this decrease. Moreover, 18F-FDG PET imaging successfully differentiated the FGFRi-sensitive tumor xenografts from primary or acquired resistant ones by the tumor 18F-FDG accumulation change upon FGFRi treatment. Of note, both 18F-FDG tumor accumulation and HK2 expression could respond the administration/withdrawal of FGFRi in NCI-H1581 xenografts correspondingly. Conclusion: The novel association between the molecular mechanism (FGFR/mTOR/HK2 axis) and radiological phenotype (18F-FDG PET uptake) of FGFR-targeted therapy was demonstrated in multiple preclinical models. The adoption of 18F-FDG PET biomarker-based imaging strategy to assess response/resistance to FGFR inhibition may benefit treatment selection for cancer patients | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a 18F-FDG | |
| 650 | 4 | |a FGFR | |
| 650 | 4 | |a PET/CT | |
| 650 | 4 | |a Therapeutic Response | |
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| 650 | 7 | |a IY9XDZ35W2 |2 NLM | |
| 700 | 1 | |a Zeng, Qinghe |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Qinghui |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Xia |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Wan, Haiyan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Luting |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Yinglei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Xiaoyu |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Dongze |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Hanyi |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Sheng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Hu |e verfasserin |4 aut | |
| 700 | 1 | |a Ding, Jian |e verfasserin |4 aut | |
| 700 | 1 | |a Ai, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Ruimin |e verfasserin |4 aut | |
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