Abstract B30: Selective small molecule AXL inhibitor BGB324 overcomes acquired drug resistance in non-small cell lung carcinoma models.

Axl is a member of the TAM (Tyro3, Axl and Mer) family of receptor tyrosine kinases that regulate multiple cellular responses including cell survival, proliferation, and migration. Axl expression is associated with a variety of human cancers including non-small cell lung carcinoma (NSCLC), and is predictive of poor patient overall survival. Axl is induced by the epithelial-to-mesenchymal transition (EMT) gene program in cancer cells. Axl signaling is required to maintain EMT-associated features including invasiveness, metastasis, and can confer resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), as well as other chemotherapeutic agents. BGB324 is a potent, reversible and selective small molecule inhibitor of Axl that has recently entered into phase I clinical trials. We evaluated the effects of BGB324 on NSCLC cells in in vitro 3D assays and in mouse xenograft models, in combination with targeted and chemotherapeutic agents. BGB324 in combination with EGFR TKI erlotinib demonstrated a synergistic anti-proliferation effect on NCI-H1299 (mesenchymal, EGFR wild-type, erlotinib-resistant) human NSCLC cells in 3D culture. In mouse xenograft models using NCI-H1299 cells BGB324 treatment significantly enhanced the antitumor acitivity of Docetaxel. Similarly, using the mesenchymal NSCLC cell line A549 (EGFR wild-type), the combination of BGB324 with either erlotinib or anti-VEGF agent bevacizumab showed synergistic or additive anti-tumour activity. Furthermore, in HCC827 (EGFR mutant, erlotinib-sensitive) human NSCLC xenograft model, addition of BGB324 treatment strikely delayed the emergence of acquired resistance to erlotinib. Taken together, these data suggest the first-in-class selective Axl inhibitor BGB324 can overcome acquired resistance in in vivo models of NSCLC. Studies in human NSCLC patient-derived xenograft models and mechanisms of action are in progress.

Citation Format: Katarzyna Wnuk-Lipinska, Gro Gausdal, Tone Sandal, Robin Frink, Stefan Hinz, Monica Hellesøy, Lavina Ahmed, Hallvard Haugen, Hallvard Haugen, Liang Xiao, Magnus Blø, David Micklem, John Minna, Rolf Brekken, Longen Zhou, James Lorens. Selective small molecule AXL inhibitor BGB324 overcomes acquired drug resistance in non-small cell lung carcinoma models. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr B30.