Abstract 3577: Sensitivity and resistance of non-small cell lung cancer to the telomerase inhibitor imetelstat

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Telomerase is expressed in the majority of lung cancers and functions to extend telomeres allowing for unlimited replication potential. Telomerase may also be essential in maintaining a cancer stem cell population making it an attractive therapeutic target. A new telomerase inhibitor, imetelstat (GRN163L), is currently in clinical trials for non-small cell lung cancer (NSCLC). Imetelstat, a lipidated 13-mer oligonucleotide N3′ P5′-thio-phosphoramidate, binds the functional RNA template of telomerase preventing telomerase from extending telomeres and thus potentially leading to telomere loss associated cancer cell death. In the present studies we treated multiple NSCLC cell lines (representing the full spectrum of oncogenotypes and chemotherapy drug response phenotypes) with imetelstat (1 μM, a concentration achieved in patients) continuously over several months and all tumor lines showed loss of telomerase activity and shortening of telomeres. NSCLC lines with initially short telomeres (NCI-H2073-initial telomere length (ITL) 2.7 Kb, Calu-3 (ITL 1.5 Kb), and NCI-H2087 (ITL 3 Kb)) either suffered massive apoptotic associated cell death (H2073) within one week, or developed very short telomeres and ceased proliferating at 2.5 weeks (Calu-3) or 20 weeks (H2087) of treatment, demonstrating primary sensitivity. However, a small subpopulation in H2073 continues to grow in culture in the presence of drug and is being tested for telomere length and sensitivity to higher concentrations of imetelstat. NSCLC lines with long telomeres (NCI-H1819 (ITL 15Kb) and NCI-H157 (ITL 14.5Kb)) treated with 1 µM imetelstat twice weekly for 32 weeks showed reduction of telomeres to 1.8 and 2 Kb respectively with no effect on mass culture proliferation but, in some cases, showed inhibition of colony formation. Removal of imetelstat resulted in return of telomerase activity and telomere re-growth. With continued 1 μM treatment, however, H1819 telomere length stabilized at 1.8Kb while H157 cells showed re-growth of telomeres to parental length and now requires >5 μM imetelstat to robustly inhibit telomerase. In summary, we have found a panel of NSCLC lines demonstrate several imetelstat response phenotypes: extreme initial sensitivity, maintenance of shortened telomeres with inhibition of colony formation, and acquired resistance to imetelstat therapy. We conclude that NSCLCs exhibit a diverse spectrum of responses to telomerase targeted therapy emphasizing the need to have tumor biomarker signatures for personalizing imetelstat therapy in NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3577.