Abstract 3333: The receptor tyrosine kinase AXL mediates nuclear translocation of the epidermal growth factor receptor

Abstract

Abstract The epidermal growth factor receptor (EGFR) is an important therapeutic target in patients with various cancers. Unfortunately, resistance to anti-EGFR therapeutics is common. Previous studies in our laboratory identified two mechanisms of resistance to the EGFR monoclonal antibody cetuximab: First, the nuclear translocation of EGFR bypasses the inhibitory effects of cetuximab; and second, the receptor tyrosine kinase AXL mediates cetuximab resistance by maintaining EGFR activation and downstream signaling. On the basis of these findings, we hypothesized that AXL could mediate the nuclear translocation of EGFR in the setting of cetuximab resistance. We found that NSCLC cetuximab-resistant clones and patient-derived xenografts (PDXs) had increased abundance of nuclear EGFR (nEGFR) and AXL. Cellular fractionation techniques, super resolution microscopy, and electron microcopy revealed that genetic loss of AXL diminished the nuclear translocation and accumulation of EGFR. Building on previous studies indicating that SRC family kinases (SFKs) and HER family ligands mediate the nuclear translocation of EGFR, we found that AXL knockdown down-regulated the expression of the SFKs YES and LYN, and the ligand neuregulin-1 (NRG1). Furthermore, AXL knockdown decreased the interaction between EGFR and HER3 and the nuclear abundance of HER3. Nuclear localization of EGFR could be rescued only upon simultaneous overexpression of Lyn and NRG1 in cells depleted of AXL. Collectively, these data uncover a previously unrecognized role for AXL in regulating the nuclear translocation of EGFR and suggest that AXL-mediated SFK activation and NRG1 expression are necessary and sufficient to regulate this process. Citation Format: Toni M. Brand, Mari Iida, Kelsey L. Corrigan, Cara M. Braverman, John P. Coan, Bailey G. Flanigan, Andrew P. Stein, Ravi Salgia, Jana Rolff, Randall J. Kimple, Deric L. Wheeler. The receptor tyrosine kinase AXL mediates nuclear translocation of the epidermal growth factor receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3333. doi:10.1158/1538-7445.AM2017-3333