title: Targeting mTOR in RET mutant medullary and differentiated thyroid cancer cells.
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.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Matti L
authors.initials: ML
authors.lastname: Gild
authors.forename: Iñigo
authors.initials: I
authors.lastname: Landa
authors.forename: Mabel
authors.initials: M
authors.lastname: Ryder
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Ghossein
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Knauf
authors.forename: James A
authors.initials: JA
authors.lastname: Fagin
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D002224:Carbanilides / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010671:Phenylurea Compounds; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D001583:Benzoxazoles; D002224:Carbanilides; D047428:Protein Kinase Inhibitors; D051096:Proto-Oncogene Proteins c-ret; D011743:Pyrimidines; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; C522130:NVP-AST487; D010671:Phenylurea Compounds; C546842:MTOR protein, human; C572449:sapanisertib; D000225:Adenine
keywords: RET inhibitors; drug combinations; mTOR; mTOR inhibitors; medullary thyroid carcinoma; oncogenic RET