GABP Couples Oncogene Signaling to Telomere Regulation in TERT Promoter Mutant Cancer

Telomere and telomerase regulation contributes to the onset and evolution of several tumors, including highly aggressive thyroid cancers (TCs). TCs are the most common endocrine malignancies and are generally characterized by a high rate of curability. However, a small but significant percentage develops distant metastasis or progresses into undifferentiated forms associated with bad prognosis and for which poor therapeutic options are available. Mutations in telomerase reverse transcriptase (TERT) promoter are among the most credited prognostic marker of aggressiveness in TCs. Indeed, their frequency progressively increases passing from indolent lesions to aggressive and anaplastic forms. TERT promoter mutations create binding sites for transcription factors, increasing TERT expression and telomerase activity. Furthermore, aggressiveness of TCs is associated with TERT locus amplification. These data encourage investigating telomerase regulating pathways as relevant drivers of TC development and progression to foster the identification of new therapeutics targets. Here, we summarize the current knowledge about telomere regulation and TCs, exploring both canonical and less conventional pathways. We discuss the possible role of telomere homeostasis in mediating response to cancer therapies and the possibility of using epigenetic drugs to re-evaluate the use of telomerase inhibitors. Combined treatments could be of support to currently used therapies still presenting weaknesses.

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GENE-43. TARGETING GABPb1L INHIBITS IN VIVO GROWTH OF TERT PROMOTER MUTANT GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.445 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi106-vi107

Author(s):

Alexandra Amen ◽

Rachel Lew ◽

Shawn Ren ◽

Andrew McKinney ◽

Andrew Mancini ◽

...

Keyword(s):

Telomerase Activity ◽

Tumor Burden ◽

Multiple Cancer ◽

Primary Glioblastoma ◽

Tert Promoter ◽

Catalytically Active ◽

In Vivo Growth ◽

Promoter Mutant

Abstract Understanding cancer cell immortality in primary glioblastoma (GBM) is essential for the development of more informed treatments. Multiple cancer types, including >80% of GBMs, undergo immortalization by reactivating Telomerase Reverse Transcriptase (TERT) through acquired mutations in the TERT promoter. TERT, the catalytically active and rate-limiting subunit of telomerase, functions to maintain telomeres, which cap and protect the ends of chromosomes. Our past work has demonstrated that the transcription factor GABP - and specifically its tetramer-forming isoform GABPb1L - binds and activates the mutant TERT promoter. The generation of CRISPR-induced indels in GABPb1L results in a gradual loss of cell viability in TERT promoter mutant but not TERT promoter wild type tumor cells in vitro, but the extent to which GABPb1L function is compromised in this setting is unclear. Thus, the potential for use of GABPb1L as an effective therapeutic target for TERT promoter mutant GBM requires further investigation. Here, we use CRISPR-based strategies to demonstrate that full knockout of GABPb1L is rapidly lethal in TERT promoter mutant cells in vitro, in association with a decrease in both TERT mRNA and telomerase activity. Heterozygous deletion of GABPb1L in the context of TERT promoter mutations leads to slowed growth of orthotopic xenograft tumors in mice, and prolonged survival. Additionally, inducible RNAi-mediated inhibition of GABPb1L in growing tumors is also capable of decreasing tumor burden and increasing survival, further strongly suggesting that targeting GABPb1L in patient tumors could be a viable treatment strategy. Finally, reduced GABPb1L synergizes with temozolomide (TMZ) therapy such that TMZ treatment in the context of low GABPb1L and low TERT leads to a complete ablation of orthotopic GBM xenografts. These results highlight the potential to improve disease outcomes by targeting TERT through inhibition of GABPb1L, particularly in conjunction with TMZ treatment.

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CBMT-21. TERT PROMOTER-MUTANT GLIOBLASTOMAS EXHIBIT DEPENDENCY ON TELOMERASE

Neuro-Oncology ◽

10.1093/neuonc/noz175.143 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi37-vi37

Author(s):

Elisa Aquilanti ◽

Duncan Baird ◽

Jacqueline Watson ◽

Matthew Meyerson

Keyword(s):

Genetic Approach ◽

Telomere Shortening ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Damage Response ◽

Somatic Alterations ◽

Promoter Mutations ◽

Chromatin Bridges ◽

Dna Damage Response Pathway ◽

Promoter Mutant

Abstract TERT promoter mutations are among the most common somatic alterations in cancer and they occur in about 80% of IDH-wildtype glioblastomas. TERT promoter mutations were found to reactivate telomerase by providing a novel binding site for the GABP transcription factor. While the effects of telomerase ablation are well understood in mice and somatic human cells, these effects in cancer are yet to be fully elucidated. In this study, we used a genetic approach with CRISPR-interference to knock down telomerase in TERT promoter-mutant glioblastoma cell lines. We show that this leads to a gradual and significant reduction in proliferation. This phenotype ultimately culminates in telomere crisis, with telomere shortening, activation of the DNA damage response pathway and formation of chromatin bridges. These data suggest that anti-telomerase therapy is a potential effective approach for glioblastoma tumors.

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