Oncotarget

Research Papers:

The preclinical assessment of XL388, a mTOR kinase inhibitor, as a promising anti-renal cell carcinoma agent

Zuquan Xiong, Yiwen Zang, Shan Zhong, Lujia Zou, Yishuo Wu, Shenghua Liu, Zujun Fang, Zhoujun Shen, Qiang Ding and Shanwen Chen _

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Oncotarget. 2017; 8:30151-30161. https://doi.org/10.18632/oncotarget.15620

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Abstract

Zuquan Xiong1,*, Yiwen Zang2,*, Shan Zhong1, Lujia Zou1, Yishuo Wu1, Shenghua Liu1, Zujun Fang1, Zhoujun Shen1, Qiang Ding1, Shanwen Chen1

1Department of Urology, Huashan Hospital Affiliated to Fudan University, Shanghai, China

2Department of General Surgery, Huashan Hospital Affiliated to Fudan University, Shanghai, China

*These authors have contributed equally to this work

Correspondence to:

Shanwen Chen, email: chenshanwenfd@163.com

Keywords: renal cell carcinoma (RCC), mammalian target of rapamycin (mTOR), apoptosis, XL388, MEK-ERK

Received: November 11, 2016     Accepted: January 16, 2017     Published: February 22, 2017

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.


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