title: The preclinical assessment of XL388, a mTOR kinase inhibitor, as a promising anti-renal cell carcinoma agent.
abstract: XL388 is a mammalian target of rapamycin (mTOR) kinase inhibitor. We demonstrated that XL388 inhibited survival and proliferation of renal cell carcinoma (RCC) cell lines (786-0 and A549) and primary human RCC cells. XL388 activated caspase-dependent apoptosis in the RCC cells. XL388 blocked mTOR complex 1 (mTORC1) and mTORC2 activation, and depleted hypoxia-inducible factor 1α (HIF1α) and HIF-2α expression in RCC cells. Yet, XL388 was ineffective in RCC cells with mTOR shRNA knockdown or kinase-dead mutation. Notably, XL388 was more efficient than mTORC1 inhibitors (rapamycin, everolimus and temsirolimus) in killing RCC cells. Further studies showed that activation of MEK-ERK might be a key resistance factor of XL388. Pharmacological or shRNA-mediated inhibition of MEK-ERK pathway sensitized XL388-induced cytotoxicity in RCC cells. In vivo, oral administration of XL388 inhibited in nude mice 786-0 RCC tumor growth, and its anti-tumor activity was sensitized with co-administration of the MEK-ERK inhibitor MEK162. Together, these results suggest that concurrent inhibition of mTORC1/2 by XL388 may represent a fine strategy to inhibit RCC cells.
authors.affiliation: Department of Urology, Huashan Hospital Affiliated to Fudan University, Shanghai, China.
authors.forename: Zuquan
authors.initials: Z
authors.lastname: Xiong
authors.affiliation: Department of General Surgery, Huashan Hospital Affiliated to Fudan University, Shanghai, China.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Zang
authors.affiliation: Department of Urology, Huashan Hospital Affiliated to Fudan University, Shanghai, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Zhong
authors.affiliation: Department of Urology, Huashan Hospital Affiliated to Fudan University, Shanghai, China.
authors.forename: Lujia
authors.initials: L
authors.lastname: Zou
authors.affiliation: Department of Urology, Huashan Hospital Affiliated to Fudan University, Shanghai, China.
authors.forename: Yishuo
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Urology, Huashan Hospital Affiliated to Fudan University, Shanghai, China.
authors.forename: Shenghua
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Urology, Huashan Hospital Affiliated to Fudan University, Shanghai, China.
authors.forename: Zujun
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Department of Urology, Huashan Hospital Affiliated to Fudan University, Shanghai, China.
authors.forename: Zhoujun
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Department of Urology, Huashan Hospital Affiliated to Fudan University, Shanghai, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Department of Urology, Huashan Hospital Affiliated to Fudan University, Shanghai, China.
authors.forename: Shanwen
authors.initials: S
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D013450:Sulfones; C000626295:XL388; D058570:TOR Serine-Threonine Kinases
keywords: MEK-ERK; XL388; apoptosis; mammalian target of rapamycin (mTOR); renal cell carcinoma (RCC)