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, Esra A. Akbay

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number672
JournalNature communications
Issue number1
StatePublished - Dec 2024

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


Dive into the research topics of 'A telomere-targeting drug depletes cancer initiating cells and promotes anti-tumor immunity in small cell lung cancer'. Together they form a unique fingerprint.

Cite this