BRAF mutation-selective inhibition of thyroid cancer cells by the novel MEK inhibitor RDEA119 and genetic-potentiated synergism with the mTOR inhibitor temsirolimus.

Abstract

We examined the therapeutic potential of a novel MEK inhibitor, RDEA119, and its synergism with the mTOR inhibitor, temsirolimus, in thyroid cancer cell lines. RDEA119 potently inhibited the proliferation of the 4 cell lines that harbored BRAF mutation but had no or modest effects on the other 4 cells that harbored wild-type BRAF (IC(50) of 0.034-0.217 μM vs. 1.413-34.120 μM). This inhibitory effect of RDEA119 in selected cell lines OCUT1 (BRAF V600E(+), PIK3CA H1047R(+)) and SW1376 (BRAF V600E(+)) was enhanced by combination with the mTOR inhibitor, temsirolimus. The PTEN-deficient cell FTC133 was highly sensitive to temsirolimus but insensitive to RDEA119, and simultaneous treatment with the latter enhanced the sensitivity of the cell to the former. The KAT18 (wild-type) cell was not sensitive to either drug alone but became sensitive to the combination of the 2 drugs. The drug synergy was confirmed by combination index and isobologram analyses. RDEA119 and temsirolimus also showed synergistic effects on autophagic death of OCUT1 and KAT18 cells selectively tested. Dramatic synergistic effects of the 2 drugs were also seen on the growth of FTC133 xenograft tumors in nude mice. Overall, the effects of the 2 drugs on cell proliferation or autophagic death, either alone or in combination, were more pronounced in cells that harbored genetic alterations in the MAP kinase and PI3K/Akt pathways. Thus, these results demonstrated the important therapeutic potential of the novel MEK inhibitor RDEA119 and its synergism with temsirolimus in thyroid cancer.

• Authors: Dingxie Liu, Joanna Xing, Barry Trink, Mingzhao Xing
• Journal: International journal of cancer (Int J Cancer) Vol. 127 Issue 12 Pg. 2965-73 (Dec 15 2010) ISSN: 1097-0215 [Electronic] United States
• PMID: 21351275 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 UICC.

Chemical References

• N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide
• Sulfonamides
• temsirolimus
• Diphenylamine
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• TOR Serine-Threonine Kinases
• MAP Kinase Kinase Kinases
• Sirolimus

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols
• Apoptosis (drug effects)
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Diphenylamine (analogs & derivatives, pharmacology)
• Drug Synergism
• Flow Cytometry
• Humans
• MAP Kinase Kinase Kinases (antagonists & inhibitors)
• Mice
• Mice, Nude
• Mutation (genetics)
• Proto-Oncogene Proteins B-raf (genetics)
• Sirolimus (analogs & derivatives, pharmacology)
• Sulfonamides (pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Thyroid Neoplasms (drug therapy, metabolism, pathology)
• Xenograft Model Antitumor Assays