Abstract 980: AMG 511, a potent and selective class I PI3K inhibitor, suppresses the growth of Kras mutant lung tumors in mice

Abstract

Abstract Background: Somatic activating mutations of KRAS are the most frequent genetic event in lung cancer, occurring in approximately 20% of NSCLC. KRAS activates two major oncogenic signaling pathways, the PI3K pathway and the MAPK pathway. Studies have suggested that blockade of both pathways is required to inhibit the growth of tumors driven by KRAS mutation. In this study, we investigated the effect of inhibiting solely the PI3K pathway on the growth of Kras G12D lung tumors in mice using AMG 511, a potent and selective class I PI3K inhibitor. To track tumor growth in this genetically engineered mouse model of lung carcinoma, we performed longitudinal monitoring of lung tumor burden during treatment using magnetic resonance imaging (MRI). Methods: Lox-stop-lox (LSL) Kras G12D mice were infected with Ad-Cre by intra-tracheal injection. Eight weeks after administration of virus, mice were randomized into two treatment groups and treated daily with 10 mg/kg AMG 511 or vehicle (N=11 per group). At 8, 11, and 14 weeks post-infection, mice were imaged using ultra-short echo time (UTE) MRI (N=6 vehicle, N=5 AMG 511). UTE MRI was performed with 30, 75, 150, 500, and 1000 αs echo times to visualize lung and tumor tissue. Lung borders were traced manually on MR images, and lung tumor volume was determined within the identified lung region using an intensity threshold to segment denser tumor tissue from normal lung tissue. At 14 weeks, lungs were harvested, weighed, and processed for histological analysis. Lung tissue area fraction was determined histomorphometrically from multiple step sections. UTE MRI images were correlated with histological sections from the same animal. Body weights were recorded. Results: Once daily treatment with AMG 511 at 10 mg/kg significantly inhibited the development of Kras G12D mutant lung tumors. Lung tumor volume, as assessed by UTE MRI, was reduced by 64% at 11 weeks (P<0.05) and 68% at 14 weeks (P<0.0005) post Ad-Cre infection, relative to vehicle-treated animals. The morphometric analysis of the same tissue showed a significant reduction in lung tissue area fraction that was consistent with the imaging results (up to 30% reduction, P<0.005). At the time of harvest, wet lung weights were also significantly reduced after treatment with AMG 511 (60% inhibition; P< 0.0001). AMG 511 had no effect on the bodyweights of the treated animals over the duration of the study. Conclusions: AMG 511 significantly inhibits the growth of Kras mutant lung tumors in mice, supporting the investigation of PI3K inhibition in patients with KRAS mutant tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 980. doi:1538-7445.AM2012-980