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.
Highlights
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib and erlotinib are first-line treatments for advanced non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations, and have been reported to improve the clinical outcome and quality-of-life of patients with this malignancy [1,2,3,4]
Consistent with previous observations, we found that gefitinib plus si-UCA1 treatment inhibited tumor growth, but these changes were not observed in blank control and gefitinib plus negative control (NC)-treated tumors (Figure 3E, 3F)
It is known that epigenetics especial non-coding RNAs play a key role in EGFR-TKIs resistance [20, 21]
Summary
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib and erlotinib are first-line treatments for advanced non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations, and have been reported to improve the clinical outcome and quality-of-life of patients with this malignancy [1,2,3,4]. The most common mechanism whereby acquired resistance to EGFR-TKIs develops is a secondary T790M mutation [7]. As well as this mechanism, c-MET amplification(5-10%), PIK3CA mutations(~5%), BRAF mutations(~1%) and small-cell lung cancer transformation(~5%) are associated with acquired resistance to TKIs [8,9,10]. In a previous study [16], we compared the expression of lncRNAs in gefitinib-sensitive and gefitinib-resistant human lung cancer cells by lncRNA microarray analysis, and found that some lncRNAs, including UCA1 (urothelial cancer-associated 1), were up-regulated in resistant cells
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