Targeting mTOR in RET mutant medullary and differentiated thyroid cancer cells
Open Access
- 4 July 2013
- journal article
- Published by Bioscientifica in Endocrine-Related Cancer
- Vol. 20 (5), 659-667
- https://doi.org/10.1530/ERC-13-0085
Abstract
Inhibitors of RET, a tyrosine kinase receptor encoded by a gene that is frequently mutated in medullary thyroid cancer, have emerged as promising novel therapies for the disease. Rapalogs and other mammalian target of rapamycin (mTOR) inhibitors are effective agents in patients with gastroenteropancreatic neuroendocrine tumors, which share lineage properties with medullary thyroid carcinomas. The objective of this study was to investigate the contribution of mTOR activity to RET-induced signaling and cell growth and to establish whether growth suppression is enhanced by co-targeting RET and mTOR kinase activities. Treatment of the RET mutant cell lines TT, TPC-1, and MZ-CRC-1 with AST487, a RET kinase inhibitor, suppressed growth and showed profound and sustained inhibition of mTOR signaling, which was recapitulated by siRNA-mediated RET knockdown. Inhibition of mTOR with INK128, a dual mTORC1 and mTORC2 kinase inhibitor, also resulted in marked growth suppression to levels similar to those seen with RET blockade. Moreover, combined treatment with AST487 and INK128 at low concentrations suppressed growth and induced apoptosis. These data establish mTOR as a key mediator of RET-mediated cell growth in thyroid cancer cells and provide a rationale for combinatorial treatments in thyroid cancers with oncogenic RET mutations.Keywords
This publication has 24 references indexed in Scilit:
- Pancreatic Endocrine Tumors: Expression Profiling Evidences a Role for AKT-mTOR PathwayJournal of Clinical Oncology, 2010
- Deoxyribonucleic Acid Profiling Analysis of 40 Human Thyroid Cancer Cell Lines Reveals Cross-Contamination Resulting in Cell Line Redundancy and MisidentificationJournal of Clinical Endocrinology & Metabolism, 2008
- BRAFV600E Mutation Is Associated with Preferential Sensitivity to Mitogen-Activated Protein Kinase Kinase Inhibition in Thyroid Cancer Cell LinesJournal of Clinical Endocrinology & Metabolism, 2008
- Dysregulated RET Signaling in Thyroid CancerEndocrinology and Metabolism Clinics of North America, 2008
- Selective Growth Inhibition in BRAF Mutant Thyroid Cancer by the Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244Journal of Clinical Endocrinology & Metabolism, 2007
- The RET Kinase Inhibitor NVP-AST487 Blocks Growth and Calcitonin Gene Expression through Distinct Mechanisms in Medullary Thyroid Cancer CellsCancer Research, 2007
- Apoptosis-mediated medullary thyroid cancer growth suppression by the PI3K inhibitor LY294002Surgery, 2006
- RET as a Diagnostic and Therapeutic Target in Sporadic and Hereditary Endocrine TumorsEndocrine Reviews, 2006
- Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR ComplexScience, 2005
- The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids.1998