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

Buse Eglenen-Polat, Ryan R. Kowash, Hai-Cheng Huang, Silvia Siteni, Mingrui Zhu, Kenian Chen, Matthew E. Bender, Ilgen Mender, Victor Stastny, Benjamin J. Drapkin, Prithvi Raj, John D. Minna, Lin Xu, Jerry W. Shay and Esra A. Akbay ()
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Buse Eglenen-Polat: University of Texas Southwestern Medical Center
Ryan R. Kowash: University of Texas Southwestern Medical Center
Hai-Cheng Huang: University of Texas Southwestern Medical Center
Silvia Siteni: University of Texas Southwestern Medical Center
Mingrui Zhu: University of Texas Southwestern Medical Center
Kenian Chen: University of Texas Southwestern Medical Center
Matthew E. Bender: University of Texas Southwestern Medical Center
Ilgen Mender: University of Texas Southwestern Medical Center
Victor Stastny: University of Texas Southwestern Medical Center
Benjamin J. Drapkin: Simmons Comprehensive Cancer Center
Prithvi Raj: Department of Immunology and Microbiome Research Laboratory University of Texas Southwestern
John D. Minna: Simmons Comprehensive Cancer Center
Lin Xu: University of Texas Southwestern Medical Center
Jerry W. Shay: Simmons Comprehensive Cancer Center
Esra A. Akbay: University of Texas Southwestern Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-44861-8

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