title: 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.
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.
authors.affiliation: Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University, Tongji University Medical School Cancer Institute, Shanghai, P. R. China.
authors.forename: Ningning
authors.initials: N
authors.lastname: Cheng
authors.affiliation: Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University, Tongji University Medical School Cancer Institute, Shanghai, P. R. China.
authors.forename: Weijing
authors.initials: W
authors.lastname: Cai
authors.affiliation: Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University, Tongji University Medical School Cancer Institute, Shanghai, P. R. China.
authors.forename: Shengxiang
authors.initials: S
authors.lastname: Ren
authors.affiliation: Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University, Tongji University Medical School Cancer Institute, Shanghai, P. R. China.
authors.forename: Xuefei
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University, Tongji University Medical School Cancer Institute, Shanghai, P. R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University, Tongji University Medical School Cancer Institute, Shanghai, P. R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Pan
authors.affiliation: Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University, Tongji University Medical School Cancer Institute, Shanghai, P. R. China.
authors.forename: Mingchuan
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University, Tongji University Medical School Cancer Institute, Shanghai, P. R. China.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University, Tongji University Medical School Cancer Institute, Shanghai, P. R. China.
authors.forename: Yishi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University, Tongji University Medical School Cancer Institute, Shanghai, P. R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University, Tongji University Medical School Cancer Institute, Shanghai, P. R. China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, Tongji University Medical School Cancer Institute, Shanghai, P. R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Fei
authors.affiliation: Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University, Tongji University Medical School Cancer Institute, Shanghai, P. R. China.
authors.forename: Caicun
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Medical and Pathology, University of Colorado Cancer Center, Aurora, Colorado, USA.
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D015999:Multivariate Analysis; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering; C515159:UCA1 RNA, human; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases
keywords: EGFR-TKIs; UCA1; acquired resistance; non-small cell lung cancer