Abstract 4242: Effects of dual inhibition of EGFR and Aurora A kinase in a lung cancer model

Abstract

Abstract Lung cancer is the leading cause of cancer related death in the US. Patients with advanced disease generally have a poor prognosis with a median survival of around 10 to 12 months with standard chemotherapy. Astsaturov and colleagues (2010) employed a synthetic lethal screening method and have reported that the combined inhibition of the EGFR and Aurora A kinase pathways had synergistic effect on cancer cell viability in head and neck and colon cancer cell lines suggesting a potential benefit of such combination therapy in patients. Our study aims to examine the effects of combination of erlotinib (E), an EGFR small-molecule inhibitor, and Alisertib (MLN8237, A), an inhibitor of Aurora A kinase, in lung cancer models. Treatment of two human NSCLC cell lines, A549 and H322M, with E+A showed synergistic activity in vitro. These cell lines were chosen for the xenografts studies in CB17 SCID mice. After tumors reached a volume of 100 mm3, mice were treated with E+A for three weeks. The xenografts were sensitive to growth inhibition by E (10 mg/kg/day) and A (20 mg/kg/twice daily) alone and the combination had an additive effect. In order to understand early cell signaling events in tumors treated with these agents we repeated the xenograft experiment by treating mice with a one time dosing of each drug alone and in combination. Three tumors per group were collected at 0 , 6 , 24 , or 48 hours after treatment and a panel of signaling molecules downstream of the EGFR and Aurora A kinase pathways were examined by Western blot. These included EGFR/pEGFR; HER2; HER3; MEK/pMEK; ERK/pERK; Src/pSrc and Akt/pAkt among others. Our results suggest that combined inhibition of both pathways in lung cancer cell lines and xenografts can lead to a reduced proliferative index as indicated by quantitative changes in these proteins and that this combination might be effective as a treatment strategy. A clinical trial with this combination is in progress at our center. Citation Format: Tetyana Bagnyukova, Xiaofan Pan, Jiping Zhang, Brian Egleston, Igor Astsaturov, Erica Golemis, Hossein Borghaei. Effects of dual inhibition of EGFR and Aurora A kinase in a lung cancer model. [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 4242. doi:10.1158/1538-7445.AM2014-4242