Preclinical Studies of Telomerase Inhibitor Imetelstat in Non-small Cell Lung Cancer
Frink, Robin Elizabeth
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Telomerase is expressed in ~90% of all cancers but is not expressed in most somatic cells making it an attractive target for cancer therapy. Telomerase has two essential components, a reverse transcriptase (hTERT) and an RNA template (hTR or hTERC). The RNA template is used by the reverse transcriptase to add the TTAGGG hexameric repeats to elongate telomeres and compensate for the loss of telomeres each cell division caused by the end replication problem. Imetelstat is an oligonucleotide designed to bind the hTR telomerase template component and inhibit telomerase leading to progressive telomere shortening associated senescence or cell death. The work described here examined the efficacy of imetelstat in a panel of non-small cell lung cancer (NSCLC) cell lines. Imetelstat was tested in a short-term liquid colony formation assay, a 5-day drug response assay, and long-term continuous treatment in vitro and in vivo. The panel of over 70 NSCLC cell lines used for this study ranged from 1.5 kb to 20 kb in average telomere length as well as a wide range in telomerase activity, growth rate, NSCLC subtype, and oncogenotype providing a broad basis for comparison of response to imetelstat. All cell lines tested showed inhibition to telomerase with imetelstat treatment. In liquid colony formation, a wide range of response to 3 uM imetelstat was seen. Colony formation inhibition ranged from 96% inhibition in HCC44 to H441 which shows a greater than 2-fold increase in colony forming ability in the presence of imetelstat, though not statistically significant. 1 uM imetelstat was given long-term in 8 different cell lines and telomerase inhibition and telomere shortening was observed in all cases. Continuous treatment led to a reduction in growth rate and eventual cell death in all but two cell lines and imetelstat response time varied among the cell lines based on initial telomere length and growth rate. Calu-3 had the fastest response time (11 days or as few as 2 population doublings) to see a change in growth rate and 32 population doublings for cell death in all cells. Calu-3, H1648 and HCC827 all showed reduced growth rate in the presence of imetelstat in vivo as well. Imetelstat inhibits telomerase, shortens telomeres and leads to cell death in many NSCLC cell lines both in vitro and in vivo supporting the idea of telomerase inhibition for the treatment of lung cancers.