Kras mutations increase telomerase activity and targeting telomerase is a promising therapeutic strategy for Kras-mutant NSCLC

// Weiran Liu 1, * , Yuesong Yin 2, * , Jun Wang 2, * , Bowen Shi 2 , Lianmin Zhang 2 , Dong Qian 3 , Chenguang Li 2 , Hua Zhang 2 , Shengguang Wang 2 , Jinfang Zhu 2 , Liuwei Gao 2 , Qiang Zhang 2 , Bin Jia 2 , Ligang Hao 2 , Changli Wang 2 , Bin Zhang 2 1 Department of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China 2 Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China 3 Department of radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China * These authors contributed equally to this work Correspondence to: Bin Zhang, email: binzh1028@163.com Keywords: Kras mutations, lung cancer, telomerase, telomere, chemoresistance Received: October 10, 2015      Accepted: June 06, 2016      Published: June 18, 2016 ABSTRACT As shortened telomeres inhibit tumor formation and prolong life span in a Kras G12D mouse lung cancer model, we investigated the implications of telomerase in Kras-mutant NSCLC. We found that Kras mutations increased TERT (telomerase reverse transcriptase) mRNA expression and telomerase activity and telomere length in both immortalized bronchial epithelial cells (BEAS-2B) and lung adenocarcinoma cells (Calu-3). MEK inhibition led to reduced TERT expression and telomerase activity. Furthermore, telomerase inhibitor BIBR1532 shortened telomere length and inhibited mutant Kras-induced long-term proliferation, colony formation and migration capabilities of BEAS-2B and Calu-3 cells. Importantly, BIBR1532 sensitized oncogenic Kras expressing Calu-3 cells to chemotherapeutic agents. The Calu-3-Kras G12D 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 Kras mutations increase telomerase activity and telomere length by activating the RAS/MEK pathway, which contributes to an aggressive phenotype of NSCLC. Kras mutations-induced lung tumorigenesis and chemoresistance are attenuated by telomerase inhibition. Targeting telomerase/telomere may be a promising therapeutic strategy for patients with Kras-mutant NSCLC.