Abstract 1917: Translating the therapeutic potential of AZD4547 in FGFR1-amplified non-small cell lung cancer through the use of primary lung explant models
Authors: Jingchuan Zhang, Lin Zhang, Xinying Su, Ming Li, ShuQiong Fan, XiaoLu Yin, YanPing Xu, Kunji Liu, Zhengwei Dong, Guanshan Zhu, Elaine Kilgour, Paul D. Smith, A. Nigel Brooks, Paul R. Gavine
Journal: Cancer Research (2012)

Abstract Lung cancer remains one of the most lethal and prevalent cancer types within developed nations. Despite recent advances in molecularly-targeted treatment options (epidermal growth factor and anaplastic lymphoma kinase inhibitors for EGFR mutations and EML4-ALK fusions respectively), there still remains significant therapeutic need, particularly for squamous cell lung cancer. Indeed, further molecular segmentation has been suggested recently through the discovery of frequent genetic amplification of the fibroblast growth factor receptor 1 gene (FGFR1) in squamous cell lung clinical samples. Preclinical validation of the tumour cells’ dependence on FGFR1 signaling in FGFR1-amplified lung cell lines has subsequently been confirmed, both in vitro and in vivo(1). AZD4547 is an orally bioavailable, highly selective and potent small molecule inhibitor which competes with ATP for binding to FGF receptors 1, 2 and 3, thereby inhibiting autophosphorylation and downstream signalling(2). This agent is currently in Phase I clinical studies. Cell line derived xenografts have proven utility as models for pharmacological studies (PK/PD) and as efficacy models in cases of oncogene addiction. However, the utility of cell line xenografts is limited by the lack of molecular and cellular heterogeneity. Primary explants offer the promise of better disease models through increased diversity of molecular lesions and the presence of significant stromal cell components. Characterisation of 127 Chinese NSCLC clinical samples using FGFR1 fluorescent in-situ hybridisation (FISH) analysis revealed an FGFR1 amplification rate of 13% (6/48) within squamous cell carcinoma. A bank of 26 primary lung explant tumour models were established and characterised - 4 of these harboured genetically amplified FGFR1 and corresponding high level protein expression. In vivo efficacy studies demonstrated rapid, potent and durable tumour regression in these models in response to oral daily dosing of AZD4547 (94-199% tumour growth inhibition after 2-3 weeks dosing of 12 or 25mg/kg AZD4547, all models p=&amp;lt;0.0001), correlating with pharmacodynamic modulation of FGFR signalling. Conversely, more modest anti-tumour efficacy was observed in FGFR1 non-amplified models (normal copy number and low copy gain) - (18% and 45% tumour growth inhibition after 3 weeks daily dosing of 25mg/kg AZD4547, p=0.25 and p=0.02 respectively). These data highlight the potential clinical utility of AZD4547 as a selective agent for the therapeutic treatment of squamous cell lung carcinoma harboring genetic amplification of FGFR1. 1 Weiss et al. 2010 Sci Transl Med. Dec 15;2(62):62ra93. 2 Gavine et al. 2011 AACR Annual Meeting. Abstract 3568. 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 1917. doi:1538-7445.AM2012-1917