Telomerase-Mediated Strategy for Overcoming Non–Small Cell Lung Cancer Targeted Therapy and Chemotherapy Resistance

Ilgen Mender, Ryan LaRanger, Krishna Luitel, Michael Peyton, Luc Girard, Tsung Po Lai, Kimberly Batten, Crystal Cornelius, Maithili P. Dalvi, Michael Ramirez, Wenting Du, Lani F. Wu, Steven J. Altschuler, Rolf Brekken, Elisabeth D. Martinez, John D. Minna, Woodring E. Wright, Jerry W. Shay

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6 Scopus citations

Abstract

Standard and targeted cancer therapies for late-stage cancer patients almost universally fail due to tumor heterogeneity/plasticity and intrinsic or acquired drug resistance. We used the telomerase substrate nucleoside precursor, 6-thio-2′-deoxyguanosine (6-thio-dG), to target telomerase-expressing non–small cell lung cancer cells resistant to EGFR-inhibitors and commonly used chemotherapy combinations. Colony formation assays, human xenografts as well as syngeneic and genetically engineered immune competent mouse models of lung cancer were used to test the effect of 6-thio-dG on targeted therapy– and chemotherapy-resistant lung cancer human cells and mouse models. We observed that erlotinib-, paclitaxel/carboplatin-, and gemcitabine/cisplatin-resistant cells were highly sensitive to 6-thio-dG in cell culture and in mouse models. 6-thio-dG, with a known mechanism of action, is a potential novel therapeutic approach to prolong disease control of therapy-resistant lung cancer patients with minimal toxicities.

Original languageEnglish (US)
Pages (from-to)826-837
Number of pages12
JournalNeoplasia (United States)
Volume20
Issue number8
DOIs
StatePublished - Aug 1 2018

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ASJC Scopus subject areas

  • Cancer Research

Cite this

Mender, I., LaRanger, R., Luitel, K., Peyton, M., Girard, L., Lai, T. P., Batten, K., Cornelius, C., Dalvi, M. P., Ramirez, M., Du, W., Wu, L. F., Altschuler, S. J., Brekken, R., Martinez, E. D., Minna, J. D., Wright, W. E., & Shay, J. W. (2018). Telomerase-Mediated Strategy for Overcoming Non–Small Cell Lung Cancer Targeted Therapy and Chemotherapy Resistance. Neoplasia (United States), 20(8), 826-837. https://doi.org/10.1016/j.neo.2018.06.002