A comparison of Ku0063794, a dual mTORC1 and mTORC2 inhibitor, and temsirolimus in preclinical renal cell carcinoma models.
Rapamycin analogs, temsirolimus and everolimus, are approved for the treatment of advance renal cell carcinoma (RCC). Currently approved agents inhibit mechanistic target of rapamycin (mTOR) complex 1 (mTORC1). However, the mTOR kinase exists in two distinct multiprotein complexes, mTORC1 and mTORC2, and both complexes may be critical regulators of cell metabolism, growth and proliferation. Furthermore, it has been proposed that drug resistance develops due to compensatory activation of mTORC2 signaling during treatment with temsirolimus or everolimus. We evaluated Ku0063794, which is a small molecule that inhibits both mTOR complexes. Ku0063794 was compared to temsirolimus in preclinical models for renal cell carcinoma. Ku0063794 was effective in inhibiting the phosphorylation of signaling proteins downstream of both mTORC1 and mTORC2, including p70 S6K, 4E-BP1 and Akt. Ku0063794 was more effective than temsirolimus in decreasing the viability and growth of RCC cell lines, Caki-1 and 786-O, in vitro by inducing cell cycle arrest and autophagy, but not apoptosis. However, in a xenograft model there was no difference in the inhibition of tumor growth by Ku0063794 or temsirolimus. A potential explanation is that temsirolimus has additional effects on the tumor microenvironment. Consistent with this possibility, temsirolimus, but not Ku0063794, decreased tumor angiogenesis in vivo, and decreased the viability of HUVEC (Human Umbilical Vein Endothelial Cells) cells in vitro at pharmacologically relevant concentrations. Furthermore, expression levels of VEGF and PDGF were lower in Caki-1 and 786-O cells treated with temsirolimus than cells treated with Ku0063794.
Department of Surgery/Division of Urology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Hao
H
Zhang
Dror
D
Berel
Yanping
Y
Wang
Ping
P
Li
Neil A
NA
Bhowmick
Robert A
RA
Figlin
Hyung L
HL
Kim
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D009025:Morpholines / Q000008:administration & dosage*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D009025:Morpholines; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D011743:Pyrimidines; C401859:temsirolimus; C541932:Ku 0063794; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051058:Oncogene Protein v-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus