Theranostics 2022; 12(14):6395-6408. doi:10.7150/thno.74848 This issue
1. School of Pharmacy, Nanchang University, Nanchang 330006, China.
2. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
3. Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
4. University of Chinese Academy of Sciences, Beijing 100049, China.
5. Analytical Research Center for Organic and Biological Molecules, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
6. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
7. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
8. Department of Nuclear Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
*These authors contributed equally to this article.
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.
Keywords: 18F-FDG, FGFR, Therapeutic Response, PET/CT, mTOR/HK2