TKI-addicted ROS1-rearranged cells are destined to survival or death by the intensity of ROS1 kinase activity
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 find...
Main Authors: | , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Nature Publishing Group
2017-07-01
|
Series: | Scientific Reports |
Online Access: | https://doi.org/10.1038/s41598-017-05736-9 |
id |
doaj-c2b81b6512f34d54906db2bec495e363 |
---|---|
record_format |
Article |
spelling |
doaj-c2b81b6512f34d54906db2bec495e3632020-12-08T00:08:17ZengNature Publishing GroupScientific Reports2045-23222017-07-017111710.1038/s41598-017-05736-9TKI-addicted ROS1-rearranged cells are destined to survival or death by the intensity of ROS1 kinase activityHayato Ogura0Yuka Nagatake-Kobayashi1Jun Adachi2Takeshi Tomonaga3Naoya Fujita4Ryohei Katayama5Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer ResearchDivision of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer ResearchLaboratory of Proteome Research, National Institute of Biomedical Innovation, Health and NutritionLaboratory of Proteome Research, National Institute of Biomedical Innovation, Health and NutritionDivision of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer ResearchDivision of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer ResearchAbstract 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.https://doi.org/10.1038/s41598-017-05736-9 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hayato Ogura Yuka Nagatake-Kobayashi Jun Adachi Takeshi Tomonaga Naoya Fujita Ryohei Katayama |
spellingShingle |
Hayato Ogura Yuka Nagatake-Kobayashi Jun Adachi Takeshi Tomonaga Naoya Fujita Ryohei Katayama TKI-addicted ROS1-rearranged cells are destined to survival or death by the intensity of ROS1 kinase activity Scientific Reports |
author_facet |
Hayato Ogura Yuka Nagatake-Kobayashi Jun Adachi Takeshi Tomonaga Naoya Fujita Ryohei Katayama |
author_sort |
Hayato Ogura |
title |
TKI-addicted ROS1-rearranged cells are destined to survival or death by the intensity of ROS1 kinase activity |
title_short |
TKI-addicted ROS1-rearranged cells are destined to survival or death by the intensity of ROS1 kinase activity |
title_full |
TKI-addicted ROS1-rearranged cells are destined to survival or death by the intensity of ROS1 kinase activity |
title_fullStr |
TKI-addicted ROS1-rearranged cells are destined to survival or death by the intensity of ROS1 kinase activity |
title_full_unstemmed |
TKI-addicted ROS1-rearranged cells are destined to survival or death by the intensity of ROS1 kinase activity |
title_sort |
tki-addicted ros1-rearranged cells are destined to survival or death by the intensity of ros1 kinase activity |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-07-01 |
description |
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. |
url |
https://doi.org/10.1038/s41598-017-05736-9 |
work_keys_str_mv |
AT hayatoogura tkiaddictedros1rearrangedcellsaredestinedtosurvivalordeathbytheintensityofros1kinaseactivity AT yukanagatakekobayashi tkiaddictedros1rearrangedcellsaredestinedtosurvivalordeathbytheintensityofros1kinaseactivity AT junadachi tkiaddictedros1rearrangedcellsaredestinedtosurvivalordeathbytheintensityofros1kinaseactivity AT takeshitomonaga tkiaddictedros1rearrangedcellsaredestinedtosurvivalordeathbytheintensityofros1kinaseactivity AT naoyafujita tkiaddictedros1rearrangedcellsaredestinedtosurvivalordeathbytheintensityofros1kinaseactivity AT ryoheikatayama tkiaddictedros1rearrangedcellsaredestinedtosurvivalordeathbytheintensityofros1kinaseactivity |
_version_ |
1724396740390420480 |