Lenvatinib targets PDGFR-β pericytes and inhibits synergy with thyroid carcinoma cells: novel translational insights.

Context Pericyte populations abundantly express tyrosine-kinases (TK, e.g. PDGFR-β) and impact therapeutic response. Lenvatinib is a clinically available TK inhibitor (TKI) that targets PDGFR-β. Duration of therapeutic response was shorter in patients with greater disease burden and metastasis. Patients may develop drug resistance and tumor progression. Objectives to 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 co-cultured CD90 +;PAX8 - thyroid-derived pericytes and BRAF WT/V600E-PTC-derived cells to determine effects of co-culture on paracrine communications and lenvatinib response. Results Pericyte abundance is significantly higher in BRAF V600E-PTC with hTERT mutations and copy number alterations compared to NT or BRAF 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, cholesterol metabolism. Pericyte growth is significantly increased by PDGF-BB, which activates phospho(p)-PDGFR-β, pERK1/2 and pAKT. Lenvatinib strongly inhibits pericyte viability by down-regulating MAPK, pAKT and p-p70S6-kinase downstream PDGFR-β. Critically, lenvatinib significantly induces higher BRAF WT/V600E-PTC cell death when co-cultured with pericytes, as a result of pericyte targeting via PDGFR-β. Conclusions This is the first thyroid-specific model of lenvatinib therapeutic efficacy against pericyte viability, which disadvantages BRAF WT/V600E-PTC growth. Assessing pericyte abundance in patients with PTC could be essential to selection rationales for appropriate targeted therapy with lenvatinib.