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

// Ningning Cheng 1,* , Weijing Cai 1,* , Shengxiang Ren 1 , Xuefei Li 2 , Qi Wang 1 , Hui Pan 1 , Mingchuan Zhao 1 , Jiayu Li 1 , Yishi Zhang 1 , Chao Zhao 2 , Xiaoxia Chen 1 , Ke Fei 3 , Caicun Zhou 1 and Fred R. Hirsch 4 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.