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

Abstract

As shortened telomeres inhibit tumor formation and prolong life span in a KrasG12D 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-KrasG12D 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.

• Authors: Weiran Liu, Yuesong Yin, Jun Wang, Bowen Shi, Lianmin Zhang, Dong Qian, Chenguang Li, Hua Zhang, Shengguang Wang, Jinfang Zhu, Liuwei Gao, Qiang Zhang, Bin Jia, Ligang Hao, Changli Wang, Bin Zhang
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 1 Pg. 179-190 (Jan 03 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 27329725 (Publication Type: Journal Article)

Chemical References

• Aminobenzoates
• Antineoplastic Agents
• BIBR 1532
• KRAS protein, human
• Naphthalenes
• Telomerase
• Proto-Oncogene Proteins p21(ras)

Topics

• Aminobenzoates (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Drug Resistance, Neoplasm (genetics)
• Enzyme Activation (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lung Neoplasms (drug therapy, genetics, metabolism, pathology)
• Mice
• Molecular Targeted Therapy
• Mutation
• Naphthalenes (pharmacology)
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• Signal Transduction (drug effects)
• Telomerase (antagonists & inhibitors, genetics, metabolism)
• Telomere
• Xenograft Model Antitumor Assays