|Author||Taniguchi H, Yamada T, Wang R, Tanimura K, Adachi Y, Nishiyama A, Tanimoto A, Takeuchi S, Araujo LH, Boroni M, Yoshimura A, Shiotsu S, Matsumoto I, Watanabe S, Kikuchi T, Miura S, Tanaka H, Kitazaki T, Yamaguchi H, Mukae H, Uchino J, Uehara H, Takayama K, Yano S.|
|Title||AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells.|
A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to osimertinib and the emergence of osimertinib-tolerant cells.
|MeSH||Adenocarcinoma of Lung / drug therapy* Adenocarcinoma of Lung / genetics Adenocarcinoma of Lung / pathology Adult Animals Antineoplastic Combined Chemotherapy Protocols / pharmacology* Antineoplastic Combined Chemotherapy Protocols / therapeutic use Carcinoma, Non-Small-Cell Lung / drug therapy* Carcinoma, Non-Small-Cell Lung / genetics Carcinoma, Non-Small-Cell Lung / pathology Cell Line, Tumor Cell Survival / drug effects Cell Survival / genetics Disease-Free Survival Drug Resistance, Neoplasm / genetics* ErbB Receptors / antagonists & inhibitors ErbB Receptors / genetics ErbB Receptors / metabolism Female Gene Knockdown Techniques Heterocyclic Compounds, 2-Ring / pharmacology Heterocyclic Compounds, 2-Ring / therapeutic use Humans Lung / pathology Lung Neoplasms / drug therapy* Lung Neoplasms / genetics Lung Neoplasms / pathology Male Mice Mice, Inbred NOD Mutation Neoplasm Recurrence, Local / genetics Neoplasm Recurrence, Local / pathology Neoplasm Recurrence, Local / prevention & control* Piperazines / pharmacology* Piperazines / therapeutic use Protein Kinase Inhibitors / pharmacology* Protein Kinase Inhibitors / therapeutic use Proto-Oncogene Proteins / antagonists & inhibitors Proto-Oncogene Proteins / genetics Proto-Oncogene Proteins / metabolism* Pyrazoles / pharmacology Pyrazoles / therapeutic use RNA, Small Interfering / metabolism Receptor Protein-Tyrosine Kinases / antagonists & inhibitors Receptor Protein-Tyrosine Kinases / genetics Receptor Protein-Tyrosine Kinases / metabolism* Receptor, ErbB-3 / genetics Receptor, ErbB-3 / metabolism Treatment Outcome Xenograft Model Antitumor Assays|
|Human and Animal Cells||PC-9(RCB4455)|