Telomerase-mediated Strategy for Overcoming Non-Small Cell Lung Cancer Targeted Therapy and Multi-drug Chemotherapy Resistance

Standard and targeted therapies almost universally fail due to tumor heterogeneity/plasticity leading to intrinsic or acquired drug resistance. We used the telomerase substrate precursor 6-thio-2’-deoxyguanosine (6-thio-dG) to target telomerase-expressing targeted therapy and platin-doublet chemotherapy resistant cells. We observed that erlotinib, paclitaxel/carboplatin and gemcitabine/cisplatin resistant cells are sensitive to 6-thio-dG in xenograft, syngeneic immunocompetent and genetically engineered mouse models. We also show sensitivity to 6-thio-dG on a large panel of non-small cell lung cancer cell lines (73 of 77). The 4 resistant NSCLC lines clustered together, providing a molecular signature for patients that may not respond to 6-thio-dG. We find SLC43A3 as a top candidate in this molecular signature. Thus, 6-thio-dG may prolong disease control of therapy-resistant lung cancer patients.