Abstract 913: Tert mutant promoter mouse model induces cancer progression in BrafV600E-driven thyroid tumors: A novel tool to understand the biology of telomerase-reactivated cancers

Abstract Hotspot mutations in the proximal promoter of the telomerase reverse transcriptase (TERT) gene are the first cross-cancer alterations lying in a gene regulatory region. TERT promoter mutations (TPMs) are enriched in advanced thyroid tumors and constitute markers of disease severity. TPMs enhance TERT transcription, which is otherwise silenced in adult tissues, thus reactivating a bone fide oncoprotein. To study TERT deregulation and its downstream consequences in a biologically accurate model, we generated a Tert-mutant promoter mouse model via CRISPR/Cas9 editing of the equivalent murine locus and crossed these animals with thyroid-specific BrafV600E-mutant mice. BrafV600E animals develop highly penetrant papillary thyroid tumors (PTC) by week 5, but do not progress. In contrast, BrafV600E+TertMUT animals showed an increased incidence of poorly differentiated thyroid cancers (PDTC) by 20 weeks (30% vs. 0% in BrafV600E; chi-squared P= 0.03), mimicking those exhibited by an alternative transgenic model of Tert overexpression (BrafV600E+K5-Tert; 36% PDTCs). Mouse Tert promoter mutation increased Tert transcription in vitro and in vivo, as reported in patients’ tumors carrying TPMs. Braf+Tert animals partially responded to MAPK pathway inhibition (dabrafenib plus trametinib), showing that MAPK signaling remains relevant in these specimens. Interestingly, RNA sequencing of Tert-reactivated murine thyroid tumors showed unique transcriptomic profiles (compared to BrafV600E alone), suggesting that downstream effects, other than the canonical Tert-mediated telomere maintenance, operate in cancers harboring TPMs. These cancer models of telomerase reactivation provide excellent pre-clinical settings to understand the regulatory mechanisms and biological underpinnings of TPM-induced progression of thyroid and other tumors, and to explore novel therapeutic strategies. Citation Format: Inigo Landa, Jingzhu Hao, Bin Xu, Joseph Giacalone, Zach Herbert, Maria A. Blasco, Jeffrey A. Knauf, Ronald Ghossein, James A. Fagin. Tert mutant promoter mouse model induces cancer progression in BrafV600E-driven thyroid tumors: A novel tool to understand the biology of telomerase-reactivated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 913.