title: Targeting the degradation of AXL receptor tyrosine kinase to overcome resistance in gefitinib-resistant non-small cell lung cancer.
abstract: Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, remains a major problem in non-small cell lung cancer (NSCLC) treatment. Increased activation of AXL has been identified as a novel mechanism for acquired resistance to EGFR-TKIs in NSCLC treatment. However, the cause of uncontrolled AXL expression is not fully understood. Here, we first demonstrate that AXL is overexpressed in an acquired gefitinib-resistant cell line (H292-Gef) as a result of slow turnover and that AXL is degraded by presenilin-dependent regulated intramembrane proteolysis (PS-RIP). Based on the findings, we attempted to enhance AXL degradation to overcome acquired gefitinib-resistance by the treatment of gefitinib-resistant NSCLC cells with yuanhuadine (YD), a potent antitumor agent in NSCLC. Treatment with YD effectively suppressed the cancer cell survival in vitro and in vivo. Mechanistically, YD accelerated the turnover of AXL by PS-RIP and resulted in the down-regulation of the full-length AXL. Therefore, the modulation of the proteolytic process through degradation of overexpressed AXL may be an attractive therapeutic strategy for the treatment of NSCLC and EGFR-TKI-resistant NSCLC.
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Song Yi
authors.initials: SY
authors.lastname: Bae
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Hong
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Hye-Jung
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Hyen Joo
authors.initials: HJ
authors.lastname: Park
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D011897:Random Allocation; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D020794:Receptor Protein-Tyrosine Kinases; D000077156:Gefitinib; D000094963:Axl Receptor Tyrosine Kinase
keywords: AXL; EGFR-TKI resistance; NSCLC; PS-RIP; yuanhuadine