Abstract 2370: miR-19b enhances proliferation and apoptosis resistance via the epidermal growth factor receptor signalling pathway by targeting PP2A and BIM in non-small cell lung cancer

Abstract

Abstract Background: Epidermal growth factor receptor (EGFR) mutations enable constitutive active downstream signaling of PI3K/AKT, KRAS/ERK and JAK/STAT pathways, and promote tumor progression by inducing uncontrolled proliferation, evasion of apoptosis and migration of non-small cell lung cancer (NSCLC). In addition, EGFR mutations increase the susceptibility of patients with NSCLC to tyrosine kinase inhibitor (TKI) therapy, but treated patients will invariably relapse with resistant disease. A global understanding of underlying molecular mechanisms of EGFR signaling may improve the management of NSCLC patients. Results: Here, we defined 17 miRNAs that are regulated by the PI3K/AKT branch of the EGFR signaling pathway. Bioinformatics analysis revealed that miRNAs that are dysregulated following PI3K/AKT inhibition act in a concerted manner to enhance the activity of the EGFR signaling pathway. These findings were closely mirrored by attenuation of miR-19b expression in NSCLC cell lines, where cell cycle progression, clonogenic growth and migration were reduced and apoptosis was enhanced. Conversely, miR-19b overexpression resulted in enhanced phosphorylation of ERK, AKT and STAT in EGFR mutant NSCLC cells. Co-treatment of NSCLC cells with the tyrosine kinase inhibitor (TKI) gefitinib and anti-miR-19b construct reduced migration and clonogenic growth in a synergistic manner suggesting that EGFR and miR-19b act together to control oncogenic processes. Serine/threonine phosphatase PP2A subunit PPP2R5E and BCL2L11 encoding BIM were identified as major targets of miR-19b. Consistent with this finding, PP2A activity was strongly enhanced in NSCLC transduced with anti-miR-19b, but not in cells co-transduced with anti-miR-19b and shPPP2R5E, suggesting that PPP2R5E is a major constituent of the PP2A complex. Accordingly, proliferation enhancement by miR-19b was due to targeting PPP2R5E. In contrast, apoptosis resistance was mainly due to targeting BCL2L11. Conclusion: Our results provide insight into the importance of targeting PPP2R5E and BCL2L11 by miR-19b in oncogenic processes of NSCLC. Attenuation of miR-19b expression could potentially be exploited in adjuvant therapy of EGFR mutant NSCLC. Citation Format: Erik Vassella. miR-19b enhances proliferation and apoptosis resistance via the epidermal growth factor receptor signalling pathway by targeting PP2A and BIM in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2370.