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.

Long non-coding RNA BC087858 induces non-T790M mutation acquired resistance to EGFR-TKIs by activating PI3K/AKT and MEK/ERK pathways and EMT in non-small-cell lung cancer

“…We have identified some lncRNAs including lncRNA UCA1, H19, BC200 and BC087858 were up-regulated in gefitinib-resistant human lung cancer cells by lncRNA microarray analysis [18]. Also we have demonstrated that lncRNA UCA1 may induce non-T790M acquired resistance to EGFR-TKIs by activating the AKT/mTOR pathway and EMT [24]. However, the role and mechanisms of lncRNA BC087858 in EGFR-TKIs acquired resistance remain unknown.…”

Long non-coding RNA UCA1 is a predictive biomarker of cancer

“…Future studies should focus on the clinical utility of UCA1 -based cancer diagnosis in clinical trials. In addition, UCA1 has been implicated in the acquired resistance to EGFR-TKIs in EGFR-mutant NSCLC that did not include a T790M mutation [8]. Thus, the expression of UCA1 should be evaluated before patients receive EGFR-TKIs.…”

“…However resistance to this treatment is often acquired, most commonly via a secondary T790M mutation. Cheng et al found that the lncRNA UCA1 was upregulated in resistant cells, and that overexpression of UCA1 was associated with shorter progression-free survival (PFS) in non-resistant cells [8]. Furthermore, UCA1 knockdown restored sensitivity to gefitinib in acquired-resistant NSCLC cells without the T790M mutation, and inhibited the activation of the AKT/mTOR pathway and epithelial-mesenchymal transition.…”

Emerging Role of Long Non-Coding RNAs in Non-Small Cell Lung Cancer: Progress and Prospects

“…Together, ANRIL is involved in the oncogenesis of NSCLC UCA1 UCA1 (Human urothelial Carcinoma Associated 1), an lncRNA was first identified in human bladder carcinoma with oncogenic activity [36]. Cheng et al showed that UCA1 induced NSCLC cancer cells acquired resistance to EGFR-TKIs by activating the AKT/mTOR pathway and EMT [37]. A recent study from Nie found that LncRNA-UCA1 exerts oncogenic functions in NSCLC by targeting miR-193a-3p [38].…”