Abstract 693: AXL tyrosine kinase inhibition selectively sensitizes mesenchymal cancer cells to antimitotic agents
Authors: Wilson Catherine , Pham Thinh , Ye Xiaofen , Lin Eva , Chan Sara , McNamara Erin , Neve Richard M. , Belmont Lisa , Koeppen Hartmut , Yauch Robert L. , Ashkenazi Avi , Settleman Jeff 
Published: May 2015

Abstract
Molecularly-targeted drug therapies have revolutionized cancer treatment, however, resistance remains a major limitation to their overall efficacy. Epithelial to mesenchymal transition (EMT) has been linked to acquired resistance to tyrosine kinase inhibitors (TKIs), independent of mutational resistance mechanisms. AXL is a receptor tyrosine kinase (RTK) associated with EMT that has been implicated in drug resistance, and has emerged as a candidate therapeutic target. Across 643 human cancer cell lines that were analyzed, we found that elevated AXL was strongly associated with a mesenchymal phenotype, particularly in triple negative breast cancer and non-small cell lung cancer. Here we experimentally established a model system to induced EMT by exposure to TGF-β and we observed that the resulting TGF-β-induced mesenchymal cells exhibit substantially increased AXL expression, become relatively drug-resistant to their appropriate TKI and cross-resistant to a variety of anti-cancer agents. We tested the ability of AXL inhibition to restore erlotinib sensitivity, in both a TGF-β-induced resistance model and in two different models of acquired resistance to erlotinib. Here, our observations do not support the previously reported role for AXL inhibition in overcoming acquired resistance to TKIs in the EMT context. However, in an unbiased screen of small molecule inhibitors of cancer-relevant processes, we discovered that AXL inhibition was specifically synergistic with anti-mitotic agents in killing cancer cells that had undergone EMT and demonstrated associated TKI resistance. Inhibition of AXL in combination with anti-mitotic agents enhances death in mitosis by promoting cells to enter mitosis through the down-regulation of CDK1, resulting in G2M cell cycle arrest. In summary, our findings highlight the utility of combination drug screening to reveal novel potentially useful anti-cancer drug combinations to improve clinical responses. While we did not identify a functional role for AXL in the context of acquired resistance to TKI therapies, we did observe that AXL inhibition may be an effective therapy in the context of mesenchymal tumors, specifically when used in combination with anti-mitotic agents. These findings reveal a novel therapeutic strategy for tumors displaying mesenchymal features that otherwise render them treatment-refractory.
Citation Format: Catherine Wilson, Thinh Pham, Xiaofen Ye, Eva Lin, Sara Chan, Erin McNamara, Richard M. Neve, Lisa Belmont, Hartmut Koeppen, Robert L. Yauch, Avi Ashkenazi, Jeff Settleman. AXL tyrosine kinase inhibition selectively sensitizes mesenchymal cancer cells to antimitotic agents. [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 693. doi:10.1158/1538-7445.AM2014-693