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International Journal of Molecular Sciences

International Journal of Molecular Sciences

IF: 4.9
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AST-487 Inhibits RET Kinase Driven TERT Expression in Bladder Cancer

Published:16 September 2022 DOI: 10.3390/ijms231810819 PMID: 36142729
Neeraj Agarwal, Qiong Zhou, Deepak Arya, Sébastien Rinaldetti, Jason Duex, Daniel V LaBarbera, Dan Theodorescu

Abstract

Mutations in the promoter of the human Telomerase Reverse Transcriptase (hTERT) gene are common and associated with its elevated expression in bladder cancer, melanoma, and glioblastoma. Though these mutations and TERT overexpression are associated with aggressive disease and poor outcome, an incomplete understanding of mutant TERT regulation limits treatment options directed at this gene. Herein, we unravel a signaling pathway that leads to upregulated hTERT expression resulting from the -124 bp promoter mutation, the most frequent variant across human cancer. We employed engineered bladder cancer cells that harbor a GFP insertion at the TSS region on -124 hTERT promoter for high-content screening drug discovery using a focused library of ~800 kinase inhibitors. Studies using in vitro and in vivo models prioritized AST-487, an inhibitor of the wild-type, and mutant RET (rearranged during transfection) proto-oncogene as a novel drug inhibitor of both wild-type and mutant promoter-driven hTERT expression. We also identified the RET kinase pathway, targeted by AST-487, as a novel regulator of mutant hTERT promoter-driven transcription in bladder cancer cells. Collectively, our work provides new potential precision medicine approaches for cancer patients with upregulated hTERT expression, perhaps, especially those harboring mutations in both the RET gene and the hTERT promoter, such as in thyroid cancer.

Substances (5)

Materials Related products
Procduct Name CAS Molecular Formula Supplier Price
AST 487 630124-46-8 C26H30F3N7O2 98 suppliers $30.00-$1950.00
AST 487 630124-46-8 C26H30F3N7O2 98 suppliers $30.00-$1950.00
AST 487 630124-46-8 C26H30F3N7O2 98 suppliers $30.00-$1950.00
AST 487 630124-46-8 C26H30F3N7O2 98 suppliers $30.00-$1950.00

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