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...

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Autores principales:	Hayato Ogura, Yuka Nagatake-Kobayashi, Jun Adachi, Takeshi Tomonaga, Naoya Fujita, Ryohei Katayama
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c2b81b6512f34d54906db2bec495e363
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spelling	oai:doaj.org-article:c2b81b6512f34d54906db2bec495e3632021-12-02T12:30:25ZTKI-addicted ROS1-rearranged cells are destined to survival or death by the intensity of ROS1 kinase activity10.1038/s41598-017-05736-92045-2322https://doaj.org/article/c2b81b6512f34d54906db2bec495e3632017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05736-9https://doaj.org/toc/2045-2322Abstract 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.Hayato OguraYuka Nagatake-KobayashiJun AdachiTakeshi TomonagaNaoya FujitaRyohei KatayamaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-17 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
author	Hayato Ogura Yuka Nagatake-Kobayashi Jun Adachi Takeshi Tomonaga Naoya Fujita Ryohei Katayama
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 Portfolio
publishDate	2017
url	https://doaj.org/article/c2b81b6512f34d54906db2bec495e363
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TKI-addicted ROS1-rearranged cells are destined to survival or death by the intensity of ROS1 kinase activity

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