Abstract 1917: Targeting wildtype and L858R/T790M mutant EGFR by isoliquiritigenin induces apoptosis and Inhibits tumor growth of NSCLC

Abstract

Abstract Genetic alteration of epidermal growth factor receptor (EGFR) is a high risk factor of non-small-cell lung cancer (NSCLC). Isoliquiritigenin (ILQ), a chalcone derivative, reported anti-cancer activities. In this study, we investigated the effects of ILQ on the growth of tyrosine kinase inhibitor -sensitive and -resistant NSCLC cells and elucidated its molecular mechanisms. Treatment with ILQ inhibited growth and induced apoptosis in both tyrosine kinase inhibitor-sensitive (HCC827, H1650; delE746-A750 EGFR) and -resistant (H1975; L858R/T790M EGFR) NSCLC cells. However, ILQ didn't showed the inhibitory effects of cell growth and induction of apoptosis in Met amplified-HCC827GR or K-ras mutated-A549 cells. ILQ induced apoptotic markers, the cleavage of caspase-3 and poly-(ADP ribose)-polymerase, increased expression of Bim and reduced expression of Bcl-2. ILQ inhibited the catalytic activity of both wildtype and double mutant (L858R/T790M) EGFR by kinase assay. Treatment with ILQ inhibited the anchorage-independent growth of NIH3T3 cells stably transfected with either wildtype or double-mutant EGFR with or without EGF stimulation. ILQ also reduced the phosphorylation of Akt and ERK1/2 in both TKI-sensitive and -resistant NSCLC cells in the western blotting analysis. ILQ directly bound both wildtype and double-mutant EGFR by ATP-competitive manner. Computational docking model expected that ILQ interacted with Glu762 and Met793 sites of wildtype EGFR and Lys745, Met793 and Asp855 of mutant EGFR. ILQ attenuated the tumor growth of H1975 cell xenografted athymic mice in vivo, which was caused by decreased expression of Ki-67 and diminished phosphorylation of Akt and ERK1/2. Taken together, ILQ suppresses NSCLC cell growth by directly targeting wildtype or mutant EGFR. Citation Format: Mee-Hyun Lee, Sung Keun Jung, Do Young Lim, Yong-Yeon Cho, Cheol-Jung Lee, Ji-Hong Song, Myoung Ok Kim, Sung-Hyun Kim, Ann M. Bode, Zigang Dong. Targeting wildtype and L858R/T790M mutant EGFR by isoliquiritigenin induces apoptosis and Inhibits tumor growth of NSCLC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1917. doi:10.1158/1538-7445.AM2015-1917