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Lenvatinib Targets PDGFR-beta Pericytes and Inhibits Synergy With Thyroid Carcinoma Cells: Novel Translational Insights
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Lenvatinib Targets PDGFR-beta Pericytes and Inhibits Synergy With Thyroid Carcinoma Cells: Novel Translational Insights
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Lenvatinib Targets PDGFR-beta Pericytes and Inhibits Synergy With Thyroid Carcinoma Cells: Novel Translational Insights
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Journal Article
Lenvatinib Targets PDGFR-beta Pericytes and Inhibits Synergy With Thyroid Carcinoma Cells: Novel Translational Insights
2021
Overview
Context: Pericyte populations abundantly express tyrosine kinases (eg, platelet-derived growth factor receptor-[beta] [PDGFR-[beta]]) and impact therapeutic response. Lenvatinib is a clinically available tyrosine kinase inhibitor that also targets PDGFR-[beta]. Duration of therapeutic response was shorter in patients with greater disease burden and metastasis. Patients may develop drug resistance and tumor progression. Objectives: Develop a gene signature of pericyte abundance to assess with tumor aggressiveness and determine both the response of thyroid-derived pericytes to lenvatinib and their synergies with thyroid carcinoma-derived cells. Design: Using a new gene signature, we estimated the relative abundance of pericytes in papillary thyroid carcinoma (PTC) and normal thyroid (NT) TCGA samples. We also cocultured CD90+;PAX8- thyroid-derived pericytes and BRA[F.sup.WT/V600E]-PTC-derived cells to determine effects of coculture on paracrine communications and lenvatinib response. Results: Pericyte abundance is significantly higher in BRA[F.sup.V600E]-PTC with hTERT mutations and copy number alterations compared with NT or BRA[F.sup.WT]-PTC samples, even when data are corrected for clinical-pathologic confounders. We have identified upregulated pathways important for tumor survival, immunomodulation, RNA transcription, cell-cycle regulation, and cholesterol metabolism. Pericyte growth is significantly increased by platelet-derived growth factor-BB, which activates phospho(p)-PDGFR-[beta], pERK1/2, and pAKT. Lenvatinib strongly inhibits pericyte viability by down-regulating MAPK, pAKT, and p-p70S6-kinase downstream PDGFR-[beta]. Critically, lenvatinib significantly induces higher BRA[F.sup.WT/V600E]-PTC cell death when cocultured with pericytes, as a result of pericyte targeting via PDGFR-[beta]. Conclusions: This is the first thyroid-specific model of lenvatinib therapeutic efficacy against pericyte viability, which disadvantages BRAFWT/V600E-PTC growth. Assessing pericyte abundance in patients with PTC could be essential to selection rationales for appropriate targeted therapy with lenvatinib. Key Words: thyroid cancer, pericyte, lenvatinib, PDGFR-[beta], BRA[F.sup.V600E], microenvironment
Publisher
Oxford University Press
