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Published on: January 29, 2019
Targeting telomerase reverse transcriptase with the covalent inhibitor NU-1 confers immunogenic radiation
Yue Liu1, Rick C Betori2, Joanna Pagacz1
1Ludwig Center for Metastasis Research and Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637, USA.
Abstract:
Beyond synthesizing telomere repeats, the telomerase reverse transcriptase (TERT) also serves multiple other roles supporting cancer growth. Blocking telomerase to drive telomere erosion appears impractical, but TERT's non-canonical activities have yet to be fully explored as cancer targets. Here, we used an irreversible TERT inhibitor, NU-1, to examine impacts on resistance to conventional cancer therapies. In vitro, inhibiting TERT sensitized cells to chemotherapy and radiation. NU-1 delayed repair of double-strand breaks, resulting in persistent DNA damage signaling and cellular senescence. Although NU-1 alone did not impact growth of syngeneic CT26 tumors in BALB/c mice, it dramatically enhanced the effects of radiation, leading to immune-dependent tumor elimination. Tumors displayed persistent DNA damage, suppressed proliferation, and increased activated immune infiltrate. Our studies confirm TERT's role in limiting genotoxic effects of conventional therapy but also implicate TERT as a determinant of immune evasion and therapy resistance.
Insights
This study shows that inhibiting telomerase reverse transcriptase (TERT) enhances cancer therapy effectiveness. Blocking TERT sensitizes cancer cells to chemotherapy and radiation, leading to immune-dependent tumor elimination.
Area of Science:
- Oncology
- Cancer Biology
- Immunology
Background:
- Telomerase reverse transcriptase (TERT) has canonical roles in telomere synthesis and non-canonical functions supporting cancer growth.
- Targeting TERT's non-canonical activities presents a potential strategy for cancer therapy.
- Conventional cancer therapies can be limited by resistance mechanisms, including those involving TERT.
Purpose of the Study:
- To investigate the impact of an irreversible TERT inhibitor, NU-1, on cancer cell sensitivity to conventional therapies.
- To explore TERT's role in DNA damage repair and immune evasion in the context of cancer therapy resistance.
Main Methods:
- Utilized an irreversible TERT inhibitor (NU-1) in in vitro cell culture models.
- Assessed the effects of NU-1 on chemotherapy and radiation sensitivity, DNA double-strand break repair, and cellular senescence.
- Evaluated NU-1's efficacy in combination with radiation in syngeneic mouse tumor models (CT26 tumors in BALB/c mice).
- Analyzed tumor characteristics including DNA damage, proliferation, and immune cell infiltration.
Main Results:
- In vitro, NU-1 sensitized cancer cells to chemotherapy and radiation by delaying double-strand break repair, inducing DNA damage signaling and senescence.
- In vivo, NU-1 alone did not inhibit tumor growth but significantly enhanced radiation therapy's efficacy.
- Combination therapy led to immune-dependent tumor elimination, characterized by persistent DNA damage, suppressed proliferation, and increased activated immune infiltrate.
Conclusions:
- TERT plays a critical role in mitigating the genotoxic effects of conventional cancer therapies.
- TERT inhibition is a viable strategy to overcome therapy resistance and enhance treatment outcomes.
- TERT is implicated as a key determinant of immune evasion and resistance to cancer therapies, suggesting its inhibition can potentiate anti-tumor immunity.
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