Abstract 1747: BGB324, a selective small molecule Axl kinase inhibitor to overcome EMT-associated drug resistance in carcinomas: Therapeutic rationale and early clinical studies

Abstract

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 predictive of poor patient overall survival in a variety of human cancers including triple negative breast (TNBC), pancreatic ductal adenocarcinoma (PDA) and non-small cell lung cancer (NSCLC). Axl expression is induced by the epithelial-to-mesenchymal transition (EMT) gene program in cancer cells and Axl signaling is required to maintain EMT-associated features including invasiveness, metastasis, stem cell-like traits and resistance to targeted inhibitors and other chemotherapeutic agents. BGB324/R428 is an oral, selective small molecule inhibitor of Axl that recently was evaluated in early clinical safety studies in healthy volunteers. Treatment with BGB324 up to and including 1.5 gms daily (per os) was established as being safe and well tolerated. The endpoints of the study included pharmacokinetics and safety. Bioavailability was increased in the presence of food and systemic exposure increased dose proportionately. At the highest dose the apparent elimination half-life approached four days presenting a range of dosing options. We evaluated the effects of BGB324 in preclinical models of TNBC, PDA and NSCLC, including 2D/3D cell culture and mouse xenograft models, in combination with targeted and chemotherapeutic agents. BGB324 treatment of mesenchymal carcinoma cells blocked invasiveness and enhanced chemotherapeutic efficacy. BGB324 abrogated the tumor initiation capacity of TNBC cells, an activity associated with cancer stem cells. BGB324 treatment blocked the emergence of EMT-associated acquired resistance to erlotinib in human NSCLC xenografts. Furthermore, combination treatment of BGB324 with chemotherapy inhibited the growth of human NSCLC xenografts and significantly prolonged survival in orthotopic and genetically engineered mouse models of PDA. Collectively, these data suggest that the first-in-class selective Axl inhibitor BGB324 can overcome EMT-related acquired therapeutic resistance and enhance the efficacy of multiple anti-cancer strategies. Together with the results of results of the early clinical safety studies, this provides a rationale for further clinical studies. Citation Format: Katarzyna Wnuk-Lipinska, Crina Tiron, Gro Gausdal, Tone Sandal, Robin Frink, Stefan Hinz, Monica Hellesøy, Lavina Ahmed, Hallvard Haugen, Xiao Liang, Magnus Blø, David Micklem, Murray Yule, John Minna, Longen Zhou, Rolf Brekken, James Lorens. BGB324, a selective small molecule Axl kinase inhibitor to overcome EMT-associated drug resistance in carcinomas: Therapeutic rationale and early clinical studies. [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 1747. doi:10.1158/1538-7445.AM2014-1747

AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma

“…R428 specificity for AXL has been previously evaluated (15), and this agent has now undergone successful phase Ia clinical evaluation (38). HNSCC cells were treated with increasing doses of R428 (0.001 uM – 1.0 uM) for 72-96 hours prior to performing proliferation assays.…”

“…R428, licensed as BGB324, has now undergone successful Phase Ia clinical evaluation in healthy volunteers, where it was deemed safe and well tolerated (38). While R428 is greater than 100 times more selective for AXL than several other tyrosine kinases (such as the insulin receptor, EGFR, and HER2), we cannot rule out the possibility that the anti-tumor responses observed in the current study were solely due to AXL inhibition (15).…”

Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation

“…In this context, the characterization of the role of Gas6/Axl pathway in liver fibrosis, by participating in the activation of HSC may provide a new therapeutic target, not only for liver fibrosis, but also for different chronic liver diseases. Moreover, the existence of specific Axl inhibitors [30], already in clinical trials, may facilitate the biomedical translation of our results.…”

Therapeutic Strategies Utilized in the Setting of Acquired Resistance to EGFR Tyrosine Kinase Inhibitors

“…More recently, increased AXL expression was observed in 5/26 patients (19%) of patients with AR to gefitinib (54). AXL inhibitors are in early clinical development (NCT00697632, ISRCTN00759419 and (55)).…”