RET kinase-regulated microRNA-153-3p improves therapeutic efficacy in medullary thyroid carcinoma

Lauren Jin Suk Joo, Jocelyn Weiss, Anthony J Gill, Roderick J Clifton-Bligh, Himanshu Brahmbhatt, Jennifer A MacDiarmid, Matti L Gild, Bruce Robinson, Jing Ting Zhao, Stan Sidhu
Thyroid: Official Journal of the American Thyroid Association 2019 March 30

BACKGROUND: Medullary thyroid carcinoma (MTC) presents a disproportionate number of thyroid cancer deaths due to the lack of an adjuvant treatment beyond surgery. Gain-of-function mutations of the human Rearranged during Transfection (RET) proto-oncogene have been well-established as the key driver of MTC tumorigenesis. RET has been targeted by tyrosine kinase inhibitors (TKIs), such as cabozantinib and vandetanib, however clinical results have been disappointing with regular dose reductions and inevitable progression. We aimed to identify RET-regulated microRNAs (miRNAs) and explore their potential as novel therapeutic targets.

METHODS: Small RNA-Sequencing was performed in MTC TT cells before and after RET inhibition to identify RET-regulated miRNAs of significance. In vitro gain-of-function studies were performed to investigate cellular and molecular effects of potential miRNAs on cell phenotypes. Systemic delivery of miRNA in MTC xenografts using EDVTM (EnGeneIC Dream Vector, EnGeneIC Ltd.) nanocells, targeted to epidermal growth factor receptor (EGFR) on tumor cells, was employed to assess the therapeutic potential and possible modulation of TKI responses.

RESULTS: We demonstrated the tumor suppressive role of a specific RET-regulated miRNA, microRNA-153-3p (miR-153-3p) in MTC. Targeted intravenous delivery of miR-153-3p impeded the tumor growth in MTC xenografts. Furthermore, combined treatment with miR-153-3p plus cabozantinib caused greater growth inhibition; and appeared to reverse cabozantinib resistance. Mechanistically, miR-153-3p targets ribosomal protein S6 kinase B1 (RPS6KB1) of mTOR signaling and reduced downstream phosphorylation of Bcl-2 associated death promoter (BAD).

CONCLUSION: This study provides evidence to establish systemic miRNA replacement plus TKIs as a novel therapeutic for patients with metastatic, progressive MTC.

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