Unknown

Dataset Information

0

Preclinical efficacy of dual mTORC1/2 inhibitor AZD8055 in renal cell carcinoma harboring a TFE3 gene fusion.


ABSTRACT: BACKGROUND:Renal cell carcinomas (RCC) harboring a TFE3 gene fusion (TfRCC) represent an aggressive subset of kidney tumors. Key signaling pathways of TfRCC are unknown and preclinical in vivo data are lacking. We investigated Akt/mTOR pathway activation and the preclinical efficacy of dual mTORC1/2 versus selective mTORC1 inhibition in TfRCC. METHODS:Levels of phosphorylated Akt/mTOR pathway proteins were compared by immunoblot in TfRCC and clear cell RCC (ccRCC) cell lines. Effects of the mTORC1 inhibitor, sirolimus, and the dual mTORC1/2 inhibitor, AZD8055, on Akt/mTOR activation, cell cycle progression, cell viability and cytotoxicity were compared in TfRCC cells. TfRCC xenograft tumor growth in mice was evaluated after 3-week treatment with oral AZD8055, intraperitoneal sirolimus and respective vehicle controls. RESULTS:The Akt/mTOR pathway was activated to a similar or greater degree in TfRCC than ccRCC cell lines and persisted partly during growth factor starvation, suggesting constitutive activation. Dual mTORC1/2 inhibition with AZD8055 potently inhibited TfRCC viability (IC50 = 20-50 nM) due at least in part to cell cycle arrest, while benign renal epithelial cells were relatively resistant (IC50 = 400 nM). Maximal viability reduction was greater with AZD8055 than sirolimus (80-90% versus 30-50%), as was the extent of Akt/mTOR pathway inhibition, based on significantly greater suppression of P-Akt (Ser473), P-4EBP1, P-mTOR and HIF1α. In mouse xenograft models, AZD8055 achieved significantly better tumor growth inhibition and prolonged mouse survival compared to sirolimus or vehicle controls. CONCLUSIONS:Akt/mTOR activation is common in TfRCC and a promising therapeutic target. Dual mTORC1/2 inhibition suppresses Akt/mTOR signaling more effectively than selective mTORC1 inhibition and demonstrates in vivo preclinical efficacy against TFE3-fusion renal cell carcinoma.

SUBMITTER: Kauffman EC 

PROVIDER: S-EPMC6743205 | BioStudies | 2019-01-01

REPOSITORIES: biostudies

Similar Datasets

2014-01-01 | S-EPMC3978713 | BioStudies
2019-01-01 | S-EPMC6398589 | BioStudies
2018-01-01 | S-EPMC6279468 | BioStudies
1000-01-01 | S-EPMC5765289 | BioStudies
2020-01-01 | S-EPMC7516067 | BioStudies
2010-01-01 | S-EPMC2864389 | BioStudies
2015-01-01 | S-EPMC4499403 | BioStudies
2016-01-01 | S-EPMC5094959 | BioStudies
2009-01-01 | S-EPMC3440776 | BioStudies
1000-01-01 | S-EPMC4622849 | BioStudies