Abstract 2762: Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR-activating and gatekeeper mutations

Abstract

Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, show favorable effects in EGFR mutant lung cancer. However, responders eventually develop acquired resistance almost without exception, and secondary T790M mutations in EGFR account for approximately 50% of the acquired resistance. Recent studies indicated that EGFR mutant lung cancer cells are dependent on EGFR/Akt signaling for survival even after acquired T790M secondary mutation. Akt kinase-interacting protein1 (Aki1) is a scaffold protein that binds to wild-type EGFR after EGF ligand stimulation, maintains signaling specificity, and mediates activating signal to the PI3K/PDK1/Akt pathway. We hypothesized that Aki1 may play important roles in signal transduction in EGFR mutant lung cancer cells. Here, we showed that Aki1 constitutively associates with mutant EGFR in lung cancer cells with (H1975) or without (PC-9 and HCC827) T790M secondary mutation. Silencing of Aki1 inhibited phosphorylation of Akt and S6, and induced apoptosis of EGFR mutant lung cancer cells. Treatment with Aki1 siRNA markedly inhibited growth of H1975 cells in a xenograft model. Moreover, silencing of Aki1 inhibited H1975 cell growth in combination with new generation EGFR-TKIs in vitro. Aki1 was frequently expressed in tumor cells of EGFR mutant lung cancer patients (53/56 cases), including those with acquired resistance to EGFR-TKI treatment (7/7 cases). Our data suggest that Aki1 may be a key mediator of survival signaling from mutant EGFR, and may therefore be an ideal target for EGFR mutant lung cancer patients, especially those with acquired EGFR-TKI resistance due to EGFR T790M secondary mutation. Citation Format: Tadaaki Yamada, David Paul Carbone, Shinji Takeuchi, Naoya Fujita, Seiji Yano. Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR-activating and gatekeeper mutations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2762. doi:10.1158/1538-7445.AM2014-2762