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Identification of cell type-specific correlations between ERK activity and cell viability upon treatment with ERK1/2 inhibitors.

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Title: Identification of cell type-specific correlations between ERK activity and cell viability upon treatment with ERK1/2 inhibitors.
Authors: Lebedev, Timofey D.1,2 lebedevtd@gmail.com, Khabusheva, Elmira R.1,2, Mareeva, Sofia R.1,3, Ivanenko, Karina A.1, Morozov, Alexey V.1, Spirin, Pavel V.1,2, Rubtsov, Petr M.1, Snezhkina, Anastasiya V.1, Kudryavtseva, Anna V.1,2, Sorokin, Maxim I.4,5,6, Buzdin, Anton A.3,4,5,6, Prassolov, Vladimir S.1,2
Source: Journal of Biological Chemistry. Aug2022, Vol. 298 Issue 8, p1-16. 16p.
Subjects: Protein-tyrosine kinase inhibitors, Cell lines, Colon cancer
Abstract: Increased MAPK signaling is a hallmark of various cancers and is a central regulator of cell survival. Direct ERK1/2 inhibition is considered a promising approach to avoid ERK1/2 reactivation caused by upstream kinases BRAF, MEK1/2, and KRAS, as well as by receptor tyrosine kinase inhibitors, but the dynamics and selectivity of ERK1/2 inhibitors are much less studied compared with BRAF or MEK inhibitors. Using ERK1/2 and downstream kinase ELK1 reporter cell lines of lung cancer (H1299; NRASQ61K), colon cancer (HCT-116; KRASG13D), neuroblastoma (SH-SY5Y), and leukemia (U937), we examined the relationship between ERK inhibition and drug-induced toxicity for five ERK inhibitors: SCH772984, ravoxertinib, LY3214996, ulixertinib, and VX-11e, as well as one MEK inhibitor, PD0325901. Comparing cell viability and ERK inhibition revealed different ERK dependencies for these cell lines. We identify several drugs, such as SCH772984 and VX-11e, which induce excessive toxicity not directly related to ERK1/2 inhibition in specific cell lines. We also show that PD0325901, LY3214996, and ulixertinib are prone to ERK1/2 reactivation over time. We distinguished two types of ERK1/2 reactivation: the first could be reversed by adding a fresh dose of inhibitors, while the second persists even after additional treatments. We also showed that cells that became resistant to the MEK1/2 inhibitor PD0325901 due to ERK1/2 reactivation remained sensitive to ERK1/2 inhibitor ulixertinib. Our data indicate that correlation of ERK inhibition with drug-induced toxicity in multiple cell lines may help to find more selective and effective ERK1/2 inhibitors. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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DbLabel: Engineering Source
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PubType: Academic Journal
PubTypeId: academicJournal
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  Data: Identification of cell type-specific correlations between ERK activity and cell viability upon treatment with ERK1/2 inhibitors.
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  Data: <searchLink fieldCode="AR" term="%22Lebedev%2C+Timofey+D%2E%22">Lebedev, Timofey D.</searchLink><relatesTo>1,2</relatesTo><i> lebedevtd@gmail.com</i><br /><searchLink fieldCode="AR" term="%22Khabusheva%2C+Elmira+R%2E%22">Khabusheva, Elmira R.</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Mareeva%2C+Sofia+R%2E%22">Mareeva, Sofia R.</searchLink><relatesTo>1,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Ivanenko%2C+Karina+A%2E%22">Ivanenko, Karina A.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Morozov%2C+Alexey+V%2E%22">Morozov, Alexey V.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Spirin%2C+Pavel+V%2E%22">Spirin, Pavel V.</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Rubtsov%2C+Petr+M%2E%22">Rubtsov, Petr M.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Snezhkina%2C+Anastasiya+V%2E%22">Snezhkina, Anastasiya V.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Kudryavtseva%2C+Anna+V%2E%22">Kudryavtseva, Anna V.</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Sorokin%2C+Maxim+I%2E%22">Sorokin, Maxim I.</searchLink><relatesTo>4,5,6</relatesTo><br /><searchLink fieldCode="AR" term="%22Buzdin%2C+Anton+A%2E%22">Buzdin, Anton A.</searchLink><relatesTo>3,4,5,6</relatesTo><br /><searchLink fieldCode="AR" term="%22Prassolov%2C+Vladimir+S%2E%22">Prassolov, Vladimir S.</searchLink><relatesTo>1,2</relatesTo>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. Aug2022, Vol. 298 Issue 8, p1-16. 16p.
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  Data: <searchLink fieldCode="DE" term="%22Protein-tyrosine+kinase+inhibitors%22">Protein-tyrosine kinase inhibitors</searchLink><br /><searchLink fieldCode="DE" term="%22Cell+lines%22">Cell lines</searchLink><br /><searchLink fieldCode="DE" term="%22Colon+cancer%22">Colon cancer</searchLink>
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  Data: Increased MAPK signaling is a hallmark of various cancers and is a central regulator of cell survival. Direct ERK1/2 inhibition is considered a promising approach to avoid ERK1/2 reactivation caused by upstream kinases BRAF, MEK1/2, and KRAS, as well as by receptor tyrosine kinase inhibitors, but the dynamics and selectivity of ERK1/2 inhibitors are much less studied compared with BRAF or MEK inhibitors. Using ERK1/2 and downstream kinase ELK1 reporter cell lines of lung cancer (H1299; NRASQ61K), colon cancer (HCT-116; KRASG13D), neuroblastoma (SH-SY5Y), and leukemia (U937), we examined the relationship between ERK inhibition and drug-induced toxicity for five ERK inhibitors: SCH772984, ravoxertinib, LY3214996, ulixertinib, and VX-11e, as well as one MEK inhibitor, PD0325901. Comparing cell viability and ERK inhibition revealed different ERK dependencies for these cell lines. We identify several drugs, such as SCH772984 and VX-11e, which induce excessive toxicity not directly related to ERK1/2 inhibition in specific cell lines. We also show that PD0325901, LY3214996, and ulixertinib are prone to ERK1/2 reactivation over time. We distinguished two types of ERK1/2 reactivation: the first could be reversed by adding a fresh dose of inhibitors, while the second persists even after additional treatments. We also showed that cells that became resistant to the MEK1/2 inhibitor PD0325901 due to ERK1/2 reactivation remained sensitive to ERK1/2 inhibitor ulixertinib. Our data indicate that correlation of ERK inhibition with drug-induced toxicity in multiple cell lines may help to find more selective and effective ERK1/2 inhibitors. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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      – Type: doi
        Value: 10.1016/j.jbc.2022.102226
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      – Code: eng
        Text: English
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        PageCount: 16
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    Subjects:
      – SubjectFull: Protein-tyrosine kinase inhibitors
        Type: general
      – SubjectFull: Cell lines
        Type: general
      – SubjectFull: Colon cancer
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      – TitleFull: Identification of cell type-specific correlations between ERK activity and cell viability upon treatment with ERK1/2 inhibitors.
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              Text: Aug2022
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