RRC ID 65939
Author Ogura H, Nagatake-Kobayashi Y, Adachi J, Tomonaga T, Fujita N, Katayama R.
Title TKI-addicted ROS1-rearranged cells are destined to survival or death by the intensity of ROS1 kinase activity.
Journal Sci Rep
Abstract ROS1 rearrangement is observed in 1-2% of non-small cell lung cancers (NSCLC). The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has induced marked tumour shrinkage in ROS1-rearranged cancers. However, emergence of acquired resistance to TKI is inevitable within a few years. Previous findings indicate that cabozantinib overcomes secondary mutation-mediated crizotinib-resistance in ROS1-fusion-positive cells. Here we attempted to establish cabozantinib-resistant cells by N-ethyl-N-nitrosourea mutagenesis screening using CD74-ROS1-expressing Ba/F3 cells. Two resistant cell lines with CD74-ROS1 F2004V or F2075C mutations, which are homologous to ALK F1174 or F1245 mutations, survived in the presence of a low dose of ROS1-TKI. Removal of ROS1-TKI from these TKI-addicted cells induced excessive activation of ROS1 tyrosine kinase followed by apoptosis. We succeeded in recapturing the TKI-addicted phenotype using doxycycline-inducible CD74-ROS1 mutant over-expression in Ba/F3 cells, suggesting that excessive ROS1 oncogenic signaling itself induced apoptosis instead of cell growth. Phosphoproteomic analysis and high-throughput inhibitor screening revealed that excessive ROS1 signaling in the TKI-addicted cells phosphorylated or activated apoptosis-related molecules such as FAF1 or p38. Collectively, our findings partly clarify molecular mechanisms of excessive ROS1 oncogenic signaling that mediates paradoxical induction of apoptosis.
Volume 7(1)
Pages 5519
Published 2017-7-17
DOI 10.1038/s41598-017-05736-9
PII 10.1038/s41598-017-05736-9
PMID 28717217
PMC PMC5514057
MeSH Anilides / pharmacology Antigens, Differentiation, B-Lymphocyte / genetics Antigens, Differentiation, B-Lymphocyte / metabolism Apoptosis / drug effects* Cell Line, Tumor Doxycycline / pharmacology Drug Resistance, Neoplasm / genetics Ethylnitrosourea / pharmacology Histocompatibility Antigens Class II / genetics Histocompatibility Antigens Class II / metabolism Humans Imidazoles / pharmacology Mutagenesis, Site-Directed Phosphopeptides / analysis Protein Kinase Inhibitors / pharmacology* Protein Structure, Tertiary Protein-Tyrosine Kinases / chemistry Protein-Tyrosine Kinases / genetics Protein-Tyrosine Kinases / metabolism* Proto-Oncogene Proteins / chemistry Proto-Oncogene Proteins / genetics Proto-Oncogene Proteins / metabolism* Pyridines / pharmacology Signal Transduction / drug effects Tandem Mass Spectrometry p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors p38 Mitogen-Activated Protein Kinases / metabolism
IF 3.998
Human and Animal Cells Ba/F3(RCB0805)