| Sorafenib and Mek inhibition is synergistic in medullary thyroid carcinoma in vitro. | |
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MedLine Citation:
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PMID: 22109971 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Clinical trials using kinase inhibitors have demonstrated transient partial responses and disease control in patients with progressive medullary thyroid cancer (MTC). The goal of this study was to identify potential combinatorial strategies to improve on these results using sorafenib, a multikinase inhibitor with activity in MTC, as a base compound to explore signaling that might predict synergystic interactions. Two human MTC cell lines, TT and MZ-CRC-1, which harbor endogenous C634W or M918T RET mutations, respectively, were exposed to sorafenib, everolimus, and AZD6244 alone and in combination. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide (MTT) and poly (ADP-ribose) polymerase (PARP) cleavage assays were performed to measure cell survival and apoptosis. Western blots were performed to confirm activity of the compounds and to determine possible mechanisms of resistance and predictors of synergy. As a solitary agent, sorafenib was the most active compound on MTT assay. Western blots confirmed that sorafenib, everolimus, and AZD6244 inhibited their anticipated targets. At concentrations below its IC(50), sorafenib-treated TT and MZ-CRC-1 cells demonstrated transient inhibition and then re-activation of Erk over 6 h. In concordance, synergistic effects were only identified using sorafenib in combination with the Mek inhibitor AZD6244 (P<0.001 for each cell line). Cells treated with everolimus demonstrated activation of Akt and Ret via TORC2 complex-dependent and TORC2 complex-independent mechanisms respectively. Everolimus was neither additive nor syngergistic in combination with sorafenib or AZD6244. In conclusion, sorafenib combined with a Mek inhibitor demonstrated synergy in MTC cells in vitro. Mechanisms of resistance to everolimus in MTC cells likely involved TORC2-dependent and TORC2-independent pathways. |
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Authors:
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Yoon Woo Koh; Manisha H Shah; Kitty Agarwal; Samantha K McCarty; Bon Seok Koo; Victoria J Brendel; Chaojie Wang; Kyle Porter; David Jarjoura; Motoyasu Saji; Matthew D Ringel |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2012-01-09 |
Journal Detail:
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Title: Endocrine-related cancer Volume: 19 ISSN: 1479-6821 ISO Abbreviation: Endocr. Relat. Cancer Publication Date: 2012 Feb |
Date Detail:
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Created Date: 2012-01-10 Completed Date: 2012-05-01 Revised Date: 2012-06-04 |
Medline Journal Info:
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Nlm Unique ID: 9436481 Medline TA: Endocr Relat Cancer Country: England |
Other Details:
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Languages: eng Pagination: 29-38 Citation Subset: IM |
Affiliation:
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Division of Endocrinology, Diabetes and Metabolism, The Ohio State University and The Arthur G. James Cancer Hospital, Columbus, Ohio 43210, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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administration & dosage Antineoplastic Combined Chemotherapy Protocols / pharmacology* Benzenesulfonates / administration & dosage Benzimidazoles / administration & dosage Carcinoma / drug therapy*, metabolism Cell Line, Tumor Cell Survival / drug effects Drug Synergism Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors, metabolism Humans MAP Kinase Signaling System / drug effects* Protein Kinase Inhibitors / administration & dosage Proto-Oncogene Proteins c-akt / antagonists & inhibitors, metabolism Proto-Oncogene Proteins c-ret / antagonists & inhibitors, metabolism Pyridines / administration & dosage Sirolimus / administration & dosage, analogs & derivatives TOR Serine-Threonine Kinases / antagonists & inhibitors Thyroid Neoplasms / drug therapy*, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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CA P0124570/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/AZD 6244; 0/Antineoplastic Agents; 0/Benzenesulfonates; 0/Benzimidazoles; 0/Protein Kinase Inhibitors; 0/Pyridines; 0/sorafenib; 159351-69-6/everolimus; 53123-88-9/Sirolimus; EC 2.7.1.1/MTOR protein, human; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.10.1/Proto-Oncogene Proteins c-ret; EC 2.7.10.1/RET protein, human; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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