Lenvatinib Targets PDGFR-β Pericytes and Inhibits Synergy With Thyroid Carcinoma Cells: Novel Translational Insights.

Asumi Iesato, Stephanie Li, Giovanni Roti, Michele R Hacker, Andrew H Fischer, Carmelo Nucera

Journal: The Journal of clinical endocrinology and metabolism 2021;106(12):3569-3590

PMID: 34302727

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Abstract

CONTEXT

Pericyte populations abundantly express tyrosine kinases (eg, platelet-derived growth factor receptor-β [PDGFR-β]) and impact therapeutic response. Lenvatinib is a clinically available tyrosine kinase inhibitor that also 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

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 BRAFWT/V600E-PTC-derived cells to determine effects of coculture on paracrine communications and lenvatinib response.

RESULTS

Pericyte abundance is significantly higher in BRAFV600E-PTC with hTERT mutations and copy number alterations compared with NT or BRAFWT-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-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 BRAFWT/V600E-PTC cell death when cocultured 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 BRAFWT/V600E-PTC growth. Assessing pericyte abundance in patients with PTC could be essential to selection rationales for appropriate targeted therapy with lenvatinib.

Address: Laboratory of Human Thyroid Cancers Preclinical and Translational Research, Division of Experimental Pathology, Cancer Research Institute (CRI), Cancer Center, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, MA, USA.; Department of Pathology, Center for Vascular Biology Research (CVBR), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, MA, USA.; Department of Medicine and Surgery, University of Parma, Parma, 43126, Italy.; Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, MA, USA.; Department of Pathology, UMass Memorial Medical Center, Worcester, 01605, MA, USA.; Laboratory of Human Thyroid Cancers Preclinical and Translational Research, Division of Experimental Pathology, Cancer Research Institute (CRI), Cancer Center, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, MA, USA.; Department of Pathology, Center for Vascular Biology Research (CVBR), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, 02142, MA, USA.

DOI: 10.1210/clinem/dgab552