A telomere-targeting drug depletes cancer initiating cells and promotes anti-tumor immunity in small cell lung cancer.

Autor: Eglenen-Polat B; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Simmons Comprehensive Cancer Center, Dallas, TX, USA., Kowash RR; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Simmons Comprehensive Cancer Center, Dallas, TX, USA., Huang HC; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Simmons Comprehensive Cancer Center, Dallas, TX, USA., Siteni S; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Zhu M; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Simmons Comprehensive Cancer Center, Dallas, TX, USA., Chen K; Quantitative Biomedical Research Center, Department of Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA., Bender ME; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Simmons Comprehensive Cancer Center, Dallas, TX, USA., Mender I; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Stastny V; Hamon Center for Therapeutic Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Drapkin BJ; Simmons Comprehensive Cancer Center, Dallas, TX, USA.; Hamon Center for Therapeutic Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Raj P; Department of Immunology and Microbiome Research Laboratory University of Texas Southwestern, Dallas, TX, USA., Minna JD; Simmons Comprehensive Cancer Center, Dallas, TX, USA.; Hamon Center for Therapeutic Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas TX, Medical Center, Dallas, TX, USA., Xu L; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Pediatrics University of Texas Southwestern Medical Center, Dallas, TX, USA., Shay JW; Simmons Comprehensive Cancer Center, Dallas, TX, USA.; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Akbay EA; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. esra.akbay@utsouthwestern.edu.; Simmons Comprehensive Cancer Center, Dallas, TX, USA. esra.akbay@utsouthwestern.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jan 22; Vol. 15 (1), pp. 672. Date of Electronic Publication: 2024 Jan 22.
DOI: 10.1038/s41467-024-44861-8
Abstrakt: There are few effective treatments for small cell lung cancer (SCLC) underscoring the need for innovative therapeutic approaches. This study focuses on exploiting telomerase, a critical SCLC dependency as a therapeutic target. A prominent characteristic of SCLC is their reliance on telomerase activity, a key enzyme essential for their continuous proliferation. Here we utilize a nucleoside analog, 6-Thio-2'-deoxyguanosine (6TdG) currently in phase II clinical trials, that is preferentially incorporated by telomerase into telomeres leading to telomere dysfunction. Using preclinical mouse and human derived models we find low intermittent doses of 6TdG inhibit tumor growth and reduce metastatic burden. Anti-tumor efficacy correlates with a reduction in a subpopulation of cancer initiating like cells (CICs) identified by their expression of L1CAM/CD133 and highest telomerase activity. 6TdG treatment also leads to activation of innate and adaptive anti-tumor responses. Mechanistically, 6TdG depletes CICs and induces type-I interferon signaling leading to tumor immune visibility by activating tumor cell STING signaling. We also observe increased sensitivity to irradiation after 6TdG treatment in both syngeneic and humanized SCLC xenograft models both of which are dependent on the presence of host immune cells. This study underscores the immune-enhancing and metastasis-reducing effects of 6TdG, employing a range of complementary in vitro and in vivo SCLC preclinical models providing a potential therapeutic approach to SCLC.
(© 2024. The Author(s).)
Databáze: MEDLINE
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