Abstract B031: Pan-cancer dissection of TERT promoter mutations in rare gliomas and colorectal cancer: shared vulnerabilities and therapeutic implications
TL;DR
GABP is established as a shared vulnerability in TERTp-mutant rare gliomas and CRC, nominating this axis for pan-cancer therapeutic development and targeting the non-coding oncogenic pathway downstream of TERTp may bypass the limitations of direct telomerase inhibition.
Abstract
Telomerase reverse transcriptase promoter (TERTp) mutations represent one of the most common non-coding alterations across cancers, yet their functional convergence between rare brain gliomas and colorectal cancer (CRC) remains poorly defined. We sought to identify shared TERTp-driven dependencies that could be therapeutically exploited. We integrated whole-genome sequencing, RNA-seq, and targeted TERTp genotyping from a multi-institutional cohort encompassing rare glioma subtypes (gliosarcoma, pleomorphic xanthoastrocytoma, diffuse midline glioma) and CRC. TERTp-mutant cell lines from both tumor classes were profiled for transcriptional programs and subjected to drug sensitivity screens against epigenetic and transcription factor inhibitors. TERTp mutations were present in 67% of rare gliomas and 52% of CRCs examined, and were associated with elevated telomerase activity. Cross-cancer transcriptomic analysis revealed convergent upregulation of the GABPA-GABPB1 complex downstream of mutant TERTp. Pharmacological inhibition of GABP using a small-molecule probe significantly reduced viability in TERTp-mutant organoids derived from both a rare gliosarcoma and a CRC liver metastasis, while TERTp wild-type counterparts were resistant. Moreover, the combination of a GABP inhibitor with a BET bromodomain inhibitor produced synergistic cytotoxicity across tumor types. Our results establish GABP as a shared vulnerability in TERTp-mutant rare gliomas and CRC, nominating this axis for pan-cancer therapeutic development. Targeting the non-coding oncogenic pathway downstream of TERTp may bypass the limitations of direct telomerase inhibition. Jinyu Lu. Pan-cancer dissection of TERT promoter mutations in rare gliomas and colorectal cancer: shared vulnerabilities and therapeutic implications [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr B031.