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

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.

Mechanisms of telomerase inhibition by oxidized and therapeutic dNTPs

“…NRTI inhibition of telomerase has been proposed to promote cellular senescence and features of premature aging in HIV patients undergoing long-term treatments 63 . In addition, several recent preclinical studies showed that 6-thio-dG is an effective treatment for melanoma, lung cancer, and glioblastoma in murine models, and increases telomere dysfunction and shortening 64 – 66 . Here, we uncover the mechanism by which 6-thio-dGTP compromises telomere maintenance via disrupting telomerase translocation.…”

Inducing rapid telomere irreparable damage in telomerase-expressing cancers

“…Similar results with 6-thio-dG were obtained with EGFR mutant tumor cells resistant to osimertinib. In addition, Mender et al [ 9 ] demonstrated that NSCLC cells resistant to both paclitaxel and carboplatin were sensitive to 6-thio-dG. Importantly, this report showed that 6-thio-dG was orally effective leading to TIFs and tumor shrinkage in xenograft models.…”

“…The third report examined the effects of 6-thio-dG in both targeted therapy resistant non-small cell lung cancer (NSCLC) and chemotherapy resistant NSCLC [ 9 ]. Mender and coworkers [ 9 ] showed that NSCLC cells resistant to the first-generation EGFR inhibitor, erlotinib, remained highly sensitive to 6-thio-dG even at low nanomolar concentrations. Similar results with 6-thio-dG were obtained with EGFR mutant tumor cells resistant to osimertinib.…”

In perspective: An update on telomere targeting in cancer

“…Even more importantly, 6‐thio‐dG appears to tackle the issues of acquired resistance and lack of efficacy for immune checkpoint blockade inhibitors and targeted therapies. Lately, 6‐thio‐dG exhibited an effective ability to overcome EGFR targeted‐ and platin‐doublet chemotherapy resistance in NSCLC, as well as in therapy‐resistant pediatric brain cancer . While targeted therapies have significantly improved the options available for unresectable or metastatic cancers, relapse almost always occurs through a variety of pathways that mediate acquired resistance.…”

“…Lately, 6-thio-dG exhibited an effective ability to overcome EGFR targeted-and platin-doublet chemotherapy resistance in NSCLC, as well as in therapy-resistant pediatric brain cancer. 44 While targeted therapies have significantly improved the options available for unresectable or metastatic cancers, relapse almost always occurs through a variety of pathways that mediate acquired resistance. Thus, it is hopeful that 6-thio-dG will work as a front line or salvage therapy towards targeting therapy-resistant cancer cells and may sensitize tumors that are refractory to checkpoint inhibitors providing long-term durable responses.…”