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Journal article
Early Reduction of Glucose Consumption Is a Biomarker of Kinase Inhibitor Efficacy Which Can Be Reversed with GLUT1 Overexpression in Lung Cancer Cells
Molecular imaging and biology
25 Oct 2022
PMID: 36284040
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Purpose Small molecule inhibitors that target oncogenic driver kinases are an important class of therapies for non-small cell lung cancer (NSCLC) and other malignancies. However, these therapies are not without their challenges. Each inhibitor works on only a subset of patients, the pharmacokinetics of these inhibitors is variable, and these inhibitors are associated with significant side effects. Many of these inhibitors lack non-invasive biomarkers to confirm pharmacodynamic efficacy, and our understanding of how these inhibitors block cancer cell growth remains incomplete. Limited clinical studies suggest that early (< 2 weeks after start of therapy) changes in tumor glucose consumption, measured by [F-18]FDG PET imaging, can predict therapeutic efficacy, but the scope of this strategy and functional relevance of this inhibition of glucose consumption remains understudied. Here we demonstrate that early inhibition of glucose consumption as can be measured clinically with [F-18]FDG PET is a consistent phenotype of efficacious targeted kinase inhibitors and is necessary for the subsequent inhibition of growth across models of NSCLC. Methods We tested nine NSCLC cell lines (A549, H1129, H1734, H1993, H2228, H3122, H460, HCC827, and PC9 cells) and ten targeted therapies (afatinib, buparlisib, ceritinib, cabozantinib, crizotinib, dovitinib, erlotinib, ponatinib, trametinib, and vemurafenib) across concentrations ranging from 1.6 nM to 5 mu M to evaluate whether these inhibitors block glucose consumption at 24-h post-drug treatment and cell growth at 72-h post-drug treatment. We overexpressed the facilitative glucose transporter SLC2A1 (GLUT1) to test the functional connection between blocked glucose consumption and cell growth after treatment with a kinase inhibitor. A subset of these inhibitors and cell lines were studied in vivo. Results Across the nine NSCLC cell lines, ten targeted therapies, and a range of inhibitor concentrations, whether a kinase inhibitor blocked glucose consumption at 24-h post-drug treatment strongly correlated with whether that inhibitor blocked cell growth at 72-h post-drug treatment in cell culture. These results were confirmed in vivo with [F-18]FDG PET imaging. GLUT1 overexpression blocked the kinase inhibitors from limiting glucose consumption and cell growth. Conclusions Our results demonstrate that the early inhibition of lung cancer glucose consumption in response to a kinase inhibitor is a strong biomarker of and is often required for the subsequent inhibition of cell growth. Early inhibition of glucose consumption may provide complementary information to other biomarkers in determining whether a drug will effectively limit tumor growth.
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Details
- Title
- Early Reduction of Glucose Consumption Is a Biomarker of Kinase Inhibitor Efficacy Which Can Be Reversed with GLUT1 Overexpression in Lung Cancer Cells
- Creators
- Chiara Ghezzi - University of California, Los AngelesStefani Perez - Univ Calif Los Angeles, Crump Inst Mol Imaging, Box 951770, Los Angeles, CA 90095 USAKaitlin Ryan - Univ Calif Los Angeles, Crump Inst Mol Imaging, Box 951770, Los Angeles, CA 90095 USAAlicia Wong - Univ Calif Los Angeles, Crump Inst Mol Imaging, Box 951770, Los Angeles, CA 90095 USABao Ying Chen - Univ Calif Los Angeles, Crump Inst Mol Imaging, Box 951770, Los Angeles, CA 90095 USARobert Damoiseaux - Univ Calif Los Angeles, Crump Inst Mol Imaging, Box 951770, Los Angeles, CA 90095 USAPeter M. Clark - Univ Calif Los Angeles, Crump Inst Mol Imaging, Box 951770, Los Angeles, CA 90095 USA
- Publication Details
- Molecular imaging and biology
- Publisher
- Springer Nature
- Number of pages
- 13
- Grant note
- UCLA Jonsson Comprehensive Cancer Center UCLA Jonsson Center Foundation Margaret E. Early Medical Research Trust Eugene V. Cota-Robles Fellowship UL1TR000124; 5P30 CA016042 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems; Drexel University
- Web of Science ID
- WOS:000874136100001
- Scopus ID
- 2-s2.0-85140607226
- Other Identifier
- 991019356495104721
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- Web of Science research areas
- Radiology, Nuclear Medicine & Medical Imaging