Targeting Telomerase Is The New Strategy Of Non-small Cell Lung Cancer With KRAS Mutation

Kras mutations are common drivers of non-small cell lung cancer(NSCLC).Many patients with Kras-mutant NSCLC fail to benefit from chemotherapy. As shortened telomeres inhibit tumor formation and prolong life span in a KrasG12 D mouse lung cancer model, we investigated the roles of telomerase in Kras-mutant NSCLC. We found that KrasG12 D upregulated TERT(telomerase reverse transcriptase) m RNA expression and increased telomerase activity and telomere length in both immortalized bronchial epithelial cells(BEAS-2B) and lung adenocarcinoma cells(Calu-3). TERT expression and telomerase activity were downregulated by MEK inhibitor trametinib. Furthermore, telomerase inhibitor BIBR1532 shortened telomere length and inhibited mutant KrasG12D-induced long-term proliferation, colony formation and migration capabilities. Importantly, BIBR1532 enhanced sensitivity to chemotherapeutic agents in KrasG12D-ovexpressed Calu-3 cells. The Calu-3- KrasG12 D xenograft mouse model confirmed that BIBR1532 enhanced the antitumor efficacy of paclitaxel in vivo. In addition, higher TERT expression was seen in Kras-mutant NSCLC than that with wild-type Kras. Our data suggest that KrasG12 D upregulates TERT expression by activating the RAS/MEK pathway, thereby increasing telomerase activity and telomere length, which contributes to an aggressive phenotype of NSCLC. KrasG12D-induced lung carcinogenesis and chemoresistance are attenuated by telomerase inhibition. Targeting telomerase/telomere may be a promising therapeutic strategy for patients with Kras-mutant NSCLC.