Journal
THERANOSTICS
Volume 12, Issue 14, Pages 6395-6408Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.74848
Keywords
F-18-FDG; FGFR; Therapeutic Response; PET/CT; mTOR/HK2
Categories
Funding
- National Natural Science Foundation of China [91859106, 82172001, 82173834, 81821005]
- Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning [2020CXJQ02]
- Shanghai Science and Technology Committee [20S11901400]
- Shanghai Municipal Science and Technology Major Project
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In this study, the researchers investigated the molecular mechanism and radiological phenotype of FGFR-targeted therapy in cancer patients. They found that FGFR inhibition can decrease the accumulation of F-18-FDG in FGFR-sensitive cancer cell lines by downregulating HK2 expression. They also demonstrated the effectiveness of using F-18-FDG PET imaging to differentiate between FGFRi-sensitive and resistant tumor xenografts. These findings suggest that using F-18-FDG PET as a biomarker-based imaging strategy can help assess the response and resistance to FGFR inhibition in cancer patients.
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 F-18-fluorodeoxyglucose (F-18-FDG) uptake assay. mTOR/PLCy/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 F-18-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, F-18-FDG PET imaging successfully differentiated the FGFRi-sensitive tumor xenografts from primary or acquired resistant ones by the tumor F-18-FDG accumulation change upon FGFRi treatment. Of note, both F-18-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 (F-18-FDG PET uptake) of FGFR-targeted therapy was demonstrated in multiple preclinical models. The adoption of F-18-FDG PET biomarker-based imaging strategy to assess response/resistance to FGFR inhibition may benefit treatment selection for cancer patients.
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