Major finding: miRNAs controlled by EGFR and MET affect the response to gefitinib in NSCLC.
Mechanism: miRNA-dependent inhibition of BIM and APAF1 suppresses gefitinib-induced apoptosis.
Impact: MET-induced miRNA expression may be a predictor of resistance to anti-EGFR agents.
The effectiveness of therapies targeting the epidermal growth factor receptor (EGFR) in non–small cell lung cancer (NSCLC) is ultimately limited by acquired drug resistance through mechanisms such as MET (hepatocyte growth factor receptor) overexpression. Because deregulation of microRNA (miRNA) expression contributes to tumorigenesis and possibly the response to receptor tyrosine kinase (RTK) inhibitors, Garofalo and colleagues evaluated the role of EGFR- and MET-regulated miRNAs in NSCLC progression and drug resistance. Global miRNA expression profiles obtained following stable knockdown of either EGFR or MET revealed that miR-30b, miR-30c, miR-221, and miR-222 were commonly downregulated by silencing of either RTK. The proapoptotic genes BCL2L11 (also known as BIM) and APAF1 were respectively identified as miR-30b/c and miR-221/222 target genes, and a significant negative correlation between expression of the miRNAs and their targets was observed in primary lung cancer tissues, over half of which exhibited MET overexpression. These RTK-regulated miRNAs were shown to play key roles in gefitinib resistance, as their overexpression in gefitinib-sensitive cells rendered them resistant to treatment, and their inhibition enhanced gefitinib sensitivity and blocked NSCLC tumor growth in nude mice. Importantly, mutation of the miRNA binding sites in the 3′ untranslated region of APAF1 and BIM restored gefitinib-induced apoptosis, further indicating that miRNA-dependent gene regulation has a direct impact on resistance to anti-EGFR agents in NSCLC. The authors also observed that miR-103 and miR-203, 2 other miRNAs inhibited by MET, act as tumor suppressors by inhibiting NSCLC proliferation and migration through suppression of SRC and PKC gene expression. Together, these findings demonstrate that common miRNAs participate in EGFR- and MET-induced oncogenic signaling networks and suggest that gefitinib resistance caused by MET overexpression is at least partly attributable to miRNA deregulation.
Garofalo M, Romano G, Di Leva G, Nuovo G, Jeon YJ, Ngankeu A, et al. EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers. Nat Med 2011;18:74–82.
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