The receptor tyrosine kinase AXL mediates nuclear translocation of the epidermal growth factor receptor.
Toni M BrandMari IidaKelsey L CorriganCara M BravermanJohn P CoanBailey G FlaniganAndrew P SteinRavi SalgiaJana RolffRandall J KimpleDeric L WheelerPublished in: Science signaling (2017)
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.
Keyphrases
- tyrosine kinase
- epidermal growth factor receptor
- advanced non small cell lung cancer
- small cell lung cancer
- transcription factor
- metastatic colorectal cancer
- oxidative stress
- genome wide
- dna methylation
- gene expression
- locally advanced
- induced apoptosis
- binding protein
- high throughput
- metabolic syndrome
- single cell
- insulin resistance
- small molecule
- cell proliferation
- artificial intelligence
- cell cycle arrest
- antibiotic resistance genes