UCSF

Activating mutations in the Telomerase Reverse Transcriptase (TERT) promoter are prevalent in cancer and enable limitless cell division characteristic of immortal cells1-12. Solving the immortality mechanism represents a major step towards selective reversal in cancer cells. TERT promoter mutations create a de novo E26 transformation specific (ETS) transcription factor binding motif. Here, we analyzed fifty-three cell lines representing sixteen cancer types and six recurrent TERTp mutations and found that the GA-binding protein (GABP) tetramer is responsible for promoter activation in all cases, extending prior studies on a few cancers and two hotspot mutations. Surprisingly, TERT expression is maintained after tetramer depletion. Further investigation revealed an underlying network of auto-suppression, the release from which drives TERT maintenance via upregulated GABP dimers or a paralogous tetramer. To target all three complexes, we used AlphaFold2 to design a biological proteolysis-targeting chimera to specifically degrade GABPA protein. TERT expression was abolished in a promoter mutation-specific manner, shortening telomeres and improving survival in a GBM xenograft model. The GABPB1L tetramer is, therefore, a pan-cancer, pan-mutation activator of the mutant TERT promoter, but it is replaceable. Domains shared by the three GABP complexes, rather than solely the B1L tetramer, are mutation-specific vulnerabilities.