title: RETRACTED: The receptor tyrosine kinase AXL mediates nuclear translocation of the epidermal growth factor receptor.
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.
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Toni M
authors.identifier: 0000-0002-6771-1283
authors.initials: TM
authors.lastname: Brand
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Iida
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Kelsey L
authors.initials: KL
authors.lastname: Corrigan
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Cara M
authors.initials: CM
authors.lastname: Braverman
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Coan
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Bailey G
authors.initials: BG
authors.lastname: Flanigan
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Stein
authors.affiliation: Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
authors.affiliation: Experimental Pharmacology and Oncology Berlin-Buch GmbH, Robert-Roessle-Str. 10, 13125 Berlin, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Rolff
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Kimple
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA. dlwheeler@wisc.edu.
authors.forename: Deric L
authors.identifier: 0000-0001-5915-3675
authors.initials: DL
authors.lastname: Wheeler
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D000068818:Cetuximab / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018613:Microscopy, Confocal; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000970:Antineoplastic Agents; D020890:Neuregulin-1; D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D019061:src-Family Kinases; D000068818:Cetuximab; D000094963:Axl Receptor Tyrosine Kinase