RET Kinase-Regulated MicroRNA-153-3p Improves Therapeutic Efficacy in Medullary Thyroid Carcinoma
Medullary thyroid carcinoma (MTC) presents a disproportionate number of thyroid cancer deaths due to limited treatment options beyond surgery. Gain-of-function mutations of the human REarranged during Transfection ( ) proto-oncogene have been well-established as the key driver of MTC tumorigenesis....
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Published in | Thyroid (New York, N.Y.) Vol. 29; no. 6; p. 830 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
01.06.2019
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Abstract | Medullary thyroid carcinoma (MTC) presents a disproportionate number of thyroid cancer deaths due to limited treatment options beyond surgery. Gain-of-function mutations of the human REarranged during Transfection (
) 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. This study aimed to identify RET-regulated microRNAs (miRNAs) and explore their potential as novel therapeutic targets.
Small RNA sequencing was performed in MTC TT cells before and after RET inhibition to identify RET-regulated miRNAs of significance.
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 EDV™ nanocells, targeted to epidermal growth factor receptor on tumor cells, was employed to assess the therapeutic potential and possible modulation of TKI responses.
The study demonstrates 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.
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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AbstractList | Medullary thyroid carcinoma (MTC) presents a disproportionate number of thyroid cancer deaths due to limited treatment options beyond surgery. Gain-of-function mutations of the human REarranged during Transfection (
) 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. This study aimed to identify RET-regulated microRNAs (miRNAs) and explore their potential as novel therapeutic targets.
Small RNA sequencing was performed in MTC TT cells before and after RET inhibition to identify RET-regulated miRNAs of significance.
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 EDV™ nanocells, targeted to epidermal growth factor receptor on tumor cells, was employed to assess the therapeutic potential and possible modulation of TKI responses.
The study demonstrates 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.
This study provides evidence to establish systemic miRNA replacement plus TKIs as a novel therapeutic for patients with metastatic, progressive MTC. |
Author | Clifton-Bligh, Roderick Weiss, Jocelyn Zhao, Jing Ting Gild, Matti L Brahmbhatt, Himanshu Sidhu, Stan B MacDiarmid, Jennifer A Joo, Lauren Jin Suk Gill, Anthony J Robinson, Bruce G |
Author_xml | – sequence: 1 givenname: Lauren Jin Suk surname: Joo fullname: Joo, Lauren Jin Suk organization: 2 Faculty of Medicine and Health; University of Sydney, Sydney, Australia – sequence: 2 givenname: Jocelyn surname: Weiss fullname: Weiss, Jocelyn organization: 3 EnGeneIC Ltd., Lane Cove West, Sydney, Australia – sequence: 3 givenname: Anthony J surname: Gill fullname: Gill, Anthony J organization: 4 NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital and Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia – sequence: 4 givenname: Roderick surname: Clifton-Bligh fullname: Clifton-Bligh, Roderick organization: 5 Department of Endocrinology; University of Sydney, Sydney, Australia – sequence: 5 givenname: Himanshu surname: Brahmbhatt fullname: Brahmbhatt, Himanshu organization: 3 EnGeneIC Ltd., Lane Cove West, Sydney, Australia – sequence: 6 givenname: Jennifer A surname: MacDiarmid fullname: MacDiarmid, Jennifer A organization: 3 EnGeneIC Ltd., Lane Cove West, Sydney, Australia – sequence: 7 givenname: Matti L surname: Gild fullname: Gild, Matti L organization: 5 Department of Endocrinology; University of Sydney, Sydney, Australia – sequence: 8 givenname: Bruce G surname: Robinson fullname: Robinson, Bruce G organization: 5 Department of Endocrinology; University of Sydney, Sydney, Australia – sequence: 9 givenname: Jing Ting surname: Zhao fullname: Zhao, Jing Ting organization: 2 Faculty of Medicine and Health; University of Sydney, Sydney, Australia – sequence: 10 givenname: Stan B surname: Sidhu fullname: Sidhu, Stan B organization: 6 University of Sydney Endocrine Surgery Unit; Royal North Shore Hospital, University of Sydney, Sydney, Australia |
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Title | RET Kinase-Regulated MicroRNA-153-3p Improves Therapeutic Efficacy in Medullary Thyroid Carcinoma |
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