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.
Highlights
Growing evidences have proposed a critical function of mammalian target of rapamycin in renal cell carcinoma (RCC) carcinogenesis and progression [1,2,3,4]
When analyzing tumor tissue samples, we showed that XL388 plus MEK162 coadministration led to concurrent inhibition of MEK-ERK and mTOR complex 1 (mTORC1)/mTORC2 (Figure 6D, blot results of three repeats were quantified)
It has been shown that the two mammalian target of rapamycin (mTOR) complexes, mTORC1 and mTORC2, are important for many cancerous behaviors of RCC [6, 14]
Summary
Growing evidences have proposed a critical function of mammalian target of rapamycin (mTOR) in renal cell carcinoma (RCC) carcinogenesis and progression [1,2,3,4]. The laterdiscovered mTORC2 is rapamycin insensitive, and is composed of mTOR, Rictor and Sin1 [5,6,7]. Both mTOR1 and mTORC2 are vital for promoting cancerous behaviors, such as cell proliferation, survival and migration as well as angiogenesis and apoptosis resistance [5,6,7]. MTORC1 inhibitors (or rapalogs), including everolimus, temsirolimus, have been tested, which demonstrated clinical benefits in metastatic RCC patients [2, 9, 10]. In the preclinical cancer studies, these inhibitors have displayed promising anticancer efficiency [4, 17,18,19,20,21,22]
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