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J. Zhu
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-004 - Inhibition of Telomerase Activity Suppresses Kras Mutation-Induced Lung Carcinogenesis and Chemoresistance (ID 2266)
09:30 - 17:00 | Author(s): J. Zhu
- Abstract
Background:
Kras mutations are one of the most common driver mutations in NSCLC, which promote lung tumorigenesis. And many patients harboring Kras mutation fail to benefit from chemotherapy. Treatment of Kras-mutant lung cancer is still a challenge. It is reported that telomere shorting inhibits tumor formation and prolongs life span in a KrasG12D mouse lung cancer model. Telomerase inhibitors show a trend toward improving survival of patients with advanced NSCLC with short telomere. However, the roles of telomerase inhibition have not been defined in Kras-mutant NSCLC.
Methods:
KrasG12D was lentivirally transduced into normal human lung cell line (BEAS-2B) and lung cancer cell lines (Calu-3 and H1299) for stable expression. The cells were transfected with TERTshRNA or treated with the telomerase inhibitor BIBR1532 to suppress the telomerase activity. Telomerase activity and telomere length were examined by the telomeric repeat amplification protocol (TRAP) assay and the Southern blot analysis of terminal restriction fragment lengths. Cell proliferation, colony formation and migration were analyzed by cell growth curves, soft agar assay and transwell migration assay. Calu-3- KrasG12D xenograft mice models were used to validate the effects of telomerase inhibition on cell growth and chemosensitivity in vivo.
Results:
We found that continuing inhibition of telomerase shorted telomere length and inhibited mutant KrasG12D-induced cell migration, colony formation, long-term proliferative capability and activation of Kras signaling pathway in both normal human lung and lung cancer cells. In addition, decreasing telomerase activity increased cells sensitivity to chemotherapeutic agents in Calu-3 and H1299 cells with KrasG12D overexpression. Notably, the effects of telomerase inhibition on Kras-mutant cells were P53 independent. In vivo experiments also confirmed treatment with telomerase inhibitor significantly enhanced tumor growth inhibition and the antitumor efficacy of chemotherapy in Calu-3-KrasG12D tumor-bearing mice.
Conclusion:
Our data suggest that Kras mutation-induced lung carcinogenesis and chemoresistance are attenuated by telomerase inhibition. Targeting telomerase/telomere may be a promising therapeutic strategy for Kras mutant NSCLC.
