PMID- 24091619 OWN - NLM STAT- MEDLINE DCOM- 20140220 LR - 20220316 IS - 1532-1827 (Electronic) IS - 0007-0920 (Print) IS - 0007-0920 (Linking) VI - 109 IP - 9 DP - 2013 Oct 29 TI - Acquired resistance to temsirolimus in human renal cell carcinoma cells is mediated by the constitutive activation of signal transduction pathways through mTORC2. PG - 2389-95 LID - 10.1038/bjc.2013.602 [doi] AB - BACKGROUND: The objective of this study was to characterise the mechanism underlying acquired resistance to temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR), in renal cell carcinoma (RCC). METHODS: A parental human RCC cell line, ACHN (ACHN/P), was continuously exposed to increasing doses of up to 20 muM of temsirolimus, and a cell line resistant to temsirolimus (ACHN/R), showing a sixfold higher IC50 than that of ACHN/P, was developed. RESULTS: Following treatment with temsirolimus, phosphorylation of S6 kinase in ACHN/P was markedly inhibited, whereas there was no detectable expression of phosphorylated S6 in ACHN/R before and after temsirolimus treatment. However, AKT and p44/42 mitogen-activated protein kinase (MAPK) were constitutively phosphorylated even after temsirolimus treatment in ACHN/R, but not in ACHN/P. There was no significant difference between the sensitivities of ACHN/P and ACHN/R to KU0063794, a dual inhibitor of mTOR complex 1 (mTORC1) and mTORC2. Similar sensitivities to temsirolimus in ACHN/P and ACHN/R could be achieved by additional treatment with specific inhibitors of AKT- and MAPK-signaling pathways. CONCLUSION: The activation of signal transduction pathways via mTORC2, but not via mTORC1, may have an important role in the acquisition of a resistant phenotype to temsirolimus in RCC. FAU - Harada, K AU - Harada K AD - Division of Urology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan. FAU - Miyake, H AU - Miyake H FAU - Kumano, M AU - Kumano M FAU - Fujisawa, M AU - Fujisawa M LA - eng PT - Journal Article DEP - 20131003 PL - England TA - Br J Cancer JT - British journal of cancer JID - 0370635 RN - 0 (Butadienes) RN - 0 (Chromones) RN - 0 (Morpholines) RN - 0 (Multiprotein Complexes) RN - 0 (Nitriles) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrimidines) RN - 0 (U 0126) RN - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - 624KN6GM2T (temsirolimus) RN - 81HJG228AB (Ku 0063794) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Apoptosis/drug effects/genetics MH - Butadienes/pharmacology MH - Carcinoma, Renal Cell/*drug therapy/genetics/metabolism MH - Cell Line, Tumor MH - Chromones/pharmacology MH - Drug Resistance, Neoplasm MH - Humans MH - Kidney Neoplasms/*drug therapy/genetics/metabolism MH - Male MH - Mechanistic Target of Rapamycin Complex 1 MH - Mechanistic Target of Rapamycin Complex 2 MH - Mice, Inbred BALB C MH - Mice, Nude MH - Mitogen-Activated Protein Kinases/genetics/metabolism MH - Morpholines/pharmacology MH - Multiprotein Complexes/genetics/*metabolism MH - Nitriles/pharmacology MH - Phosphorylation/drug effects MH - Protein Kinase Inhibitors/pharmacology MH - Proto-Oncogene Proteins c-akt/genetics/metabolism MH - Pyrimidines/pharmacology MH - Ribosomal Protein S6 Kinases/genetics MH - Signal Transduction/drug effects MH - Sirolimus/*analogs & derivatives/pharmacology MH - TOR Serine-Threonine Kinases/genetics/*metabolism PMC - PMC3817337 EDAT- 2013/10/05 06:00 MHDA- 2014/02/22 06:00 PMCR- 2014/10/29 CRDT- 2013/10/05 06:00 PHST- 2013/08/10 00:00 [revised] PHST- 2013/09/11 00:00 [accepted] PHST- 2013/10/05 06:00 [entrez] PHST- 2013/10/05 06:00 [pubmed] PHST- 2014/02/22 06:00 [medline] PHST- 2014/10/29 00:00 [pmc-release] AID - bjc2013602 [pii] AID - 10.1038/bjc.2013.602 [doi] PST - ppublish SO - Br J Cancer. 2013 Oct 29;109(9):2389-95. doi: 10.1038/bjc.2013.602. Epub 2013 Oct 3.