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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Promoter mutations in the human Telomerase Reverse Transcriptase (hTERT) gene are frequently observed in cancers like bladder cancer, melanoma, and glioblastoma.
• Elevated hTERT expression due to these mutations correlates with aggressive disease and poorer patient outcomes, yet regulatory mechanisms remain poorly understood.

Purpose of the Study:

• To elucidate the signaling pathway responsible for upregulated hTERT expression driven by the common -124 bp promoter mutation.
• To identify novel therapeutic targets and drugs for cancers with aberrant hTERT expression.

Main Methods:

• Utilized engineered bladder cancer cells with a GFP insertion at the transcription start site (TSS) of the -124 hTERT promoter for high-content screening.
• Screened a focused library of approximately 800 kinase inhibitors to identify modulators of hTERT expression.
• Validated findings using in vitro and in vivo models, including assessment of AST-487, a RET proto-oncogene inhibitor.

Main Results:

• Discovered that the RET kinase pathway regulates hTERT transcription driven by the -124 bp promoter mutation in bladder cancer cells.
• Identified AST-487, a RET inhibitor, as a novel agent capable of inhibiting hTERT expression driven by both wild-type and mutant hTERT promoters.
• Demonstrated that AST-487 effectively reduces hTERT expression in both in vitro and in vivo models.

Conclusions:

• The RET kinase pathway is a novel regulator of mutant hTERT promoter-driven transcription, particularly in bladder cancer.
• AST-487 shows promise as a therapeutic agent for cancers with upregulated hTERT expression, especially those with co-occurring RET and hTERT promoter mutations.
• This research opens avenues for precision medicine strategies targeting specific genetic alterations in cancer treatment.