Research Papers:
Long non-coding RNA UCA1 induces non-T790M acquired resistance to EGFR-TKIs by activating the AKT/mTOR pathway in EGFR-mutant non-small cell lung cancer
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Abstract
Ningning Cheng1,*, Weijing Cai1,*, Shengxiang Ren1, Xuefei Li2, Qi Wang1, Hui Pan1, Mingchuan Zhao1, Jiayu Li1, Yishi Zhang1, Chao Zhao2, Xiaoxia Chen1, Ke Fei3, Caicun Zhou1 and Fred R. Hirsch4
1 Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University, Tongji University Medical School Cancer Institute, Shanghai, P. R. China
2 Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University, Tongji University Medical School Cancer Institute, Shanghai, P. R. China
3 Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, Tongji University Medical School Cancer Institute, Shanghai, P. R. China
4 Department of Medical and Pathology, University of Colorado Cancer Center, Aurora, Colorado, USA
* These authors have contributed equally to this work
Correspondence to:
Caicun Zhou, email:
Keywords: UCA1, EGFR-TKIs, acquired resistance, non-small cell lung cancer
Received: February 09, 2015 Accepted: June 01, 2015 Published: June 08, 2015
Abstract
The aim of this study was to explore the role of long non-coding RNA UCA1 (urothelial cancer-associated 1) in acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). In our study, UCA1 expression was significantly increased in lung cancer cells and patients with acquired resistance to EGFR-TKIs. Over-expression of UCA1 was significantly associated with a shorter progression-free survival (PFS) [13.0 vs. 8.5 months, P < 0.01] in tumors with respond to EGFR-TKIs. The significant relationship was not observed in patients with T790M mutation (10.5 vs. 12.0 months, P = 0.778), but in patients with non-T790M (19.0 vs. 9.0 months, P = 0.023). UCA1 knockdown restored gefitinib sensitivity in acquired resistant cells with non-T790M and inhibited the activation of the AKT/mTOR pathway and epithelial-mesenchymal transition (EMT). The mTOR inhibitor was effective in UCA1-expressing cell PC9/R. Inhibiting mTOR could change the expression of UCA1, although there was no significant difference. In conclusion, the influence of over-expression of UCA1 on PFS for patients with acquired resistance to EGFR-TKIs was from the subgroup with non-T790M mutation. UCA1 may induce non-T790M acquired resistance to EGFR-TKIs by activating the AKT/mTOR pathway and EMT.
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