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Neoplasia. 2018 Aug;20(8):826-837. doi: 10.1016/j.neo.2018.06.002. Epub 2018 Jul 6.

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

Author information

1
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA.
4
Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
5
Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
6
Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA.
7
Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Division of Surgical Oncology, Department of Surgery and Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX.
8
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; Division of Surgical Oncology, Department of Surgery and Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX.
9
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA.
10
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: jerry.shay@utsouthwestern.edu.

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.

PMID:
30015158
PMCID:
PMC6037876
DOI:
10.1016/j.neo.2018.06.002
[Indexed for MEDLINE]
Free PMC Article

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