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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.
