Research ArticleCancer

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

Sci. Signal.  03 Jan 2017:
Vol. 10, Issue 460,
DOI: 10.1126/scisignal.aag1064

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AXL sends EGFR to the nucleus

The receptor tyrosine kinase (RTK) EGFR drives the growth of various cancers. Although a transmembrane protein that detects extracellular signals, EGFR accumulates at the nucleus in advanced and aggressive tumors. The abundance and activity of another RTK, AXL, is correlated with EGFR activation and drug resistance. Using patient-derived xenografts and lung cancer cell lines that were resistant or sensitive to cetuximab (an antibody that inhibits EGFR activity), Brand et al. found that AXL increases the expression of genes encoding the EGFR family ligand neuregulin-1 and two non-RTKs, YES and LYN. In the absence of AXL, nuclear accumulation of EGFR was blocked but was restored by overexpressing YES or LYN or adding neuregulin-1 to the cultures. Thus, ligand-mediated activation of EGFR in the context of enhanced non-RTK activity triggers the nuclear accumulation of EGFR, providing resistance to antibody therapies that target the extracellular part of EGFR. This study reveals a connection between an RTK and non-RTKs in resistance to rational targeted cancer therapies.

Abstract

The epidermal growth factor receptor (EGFR) is a therapeutic target in patients with various cancers. Unfortunately, resistance to EGFR-targeted therapeutics is common. Previous studies identified two mechanisms of resistance to the EGFR monoclonal antibody cetuximab. Nuclear translocation of EGFR bypasses the inhibitory effects of cetuximab, and the receptor tyrosine kinase AXL mediates cetuximab resistance by maintaining EGFR activation and downstream signaling. Thus, we hypothesized that AXL mediated the nuclear translocation of EGFR in the setting of cetuximab resistance. Cetuximab-resistant clones of non–small cell lung cancer in culture and patient-derived xenografts in mice had increased abundance of AXL and nuclear EGFR (nEGFR). Cellular fractionation analysis, super-resolution microscopy, and electron microscopy revealed that genetic loss of AXL reduced the accumulation of nEGFR. SRC family kinases (SFKs) and HER family ligands promote the nuclear translocation of EGFR. We found that AXL knockdown reduced the expression of the genes encoding the SFK family members YES and LYN and the ligand neuregulin-1 (NRG1). AXL knockdown also decreased the interaction between EGFR and the related receptor HER3 and accumulation of HER3 in the nucleus. Overexpression of LYN and NRG1 in cells depleted of AXL resulted in accumulation of nEGFR, rescuing the deficit induced by lack 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 and NRG1 expression promote this process.

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