Musashi-2 (MSI2) regulates epidermal growth factor receptor (EGFR) expression and response to EGFR inhibitors in EGFR-mutated non-small cell lung cancer (NSCLC)
Abstract Non-small cell lung cancer (NSCLC) has limited treatment options. Expression of the RNA-binding protein (RBP) Musashi-2 (MSI2) is elevated in a subset of non-small cell lung cancer (NSCLC) tumors upon progression, and drives NSCLC metastasis. We evaluated the mechanism of MSI2 action in NSC...
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2021-03-01
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Online Access: | https://doi.org/10.1038/s41389-021-00317-y |
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doaj-2ede848ef5274440b27190aa152d7cbe2021-03-21T12:25:31ZengNature Publishing GroupOncogenesis2157-90242021-03-0110311410.1038/s41389-021-00317-yMusashi-2 (MSI2) regulates epidermal growth factor receptor (EGFR) expression and response to EGFR inhibitors in EGFR-mutated non-small cell lung cancer (NSCLC)Petr Makhov0Igor Bychkov1Bulat Faezov2Alexander Deneka3Alexander Kudinov4Emmanuelle Nicolas5Rohan Brebion6Eleanor Avril7Kathy Q. Cai8Leonid V. Kharin9Mark Voloshin10Elena Frantsiyants11Nikolay Karnaukhov12Oleg I. Kit13Iuliia Topchu14Rushaniya Fazliyeva15Anna S. Nikonova16Ilya G. Serebriiskii17Hossein Borghaei18Martin Edelman19Essel Dulaimi20Erica A. Golemis21Yanis Boumber22Molecular Therapeutics Program, Fox Chase Cancer CenterMolecular Therapeutics Program, Fox Chase Cancer CenterMolecular Therapeutics Program, Fox Chase Cancer CenterMolecular Therapeutics Program, Fox Chase Cancer CenterMolecular Therapeutics Program, Fox Chase Cancer CenterMolecular Therapeutics Program, Fox Chase Cancer CenterTemple University School of MedicineMolecular Therapeutics Program, Fox Chase Cancer CenterHistopathology Facility, Fox Chase Cancer CenterMolecular Therapeutics Program, Fox Chase Cancer CenterRostov State Medical UniversityNational Medical research center for OncologyNational Medical research center for OncologyNational Medical research center for OncologyMolecular Therapeutics Program, Fox Chase Cancer CenterMolecular Therapeutics Program, Fox Chase Cancer CenterMolecular Therapeutics Program, Fox Chase Cancer CenterMolecular Therapeutics Program, Fox Chase Cancer CenterMolecular Therapeutics Program, Fox Chase Cancer CenterDepartment of Hematology/Oncology, Fox Chase Cancer CenterDepartment of Pathology, Fox Chase Cancer CenterMolecular Therapeutics Program, Fox Chase Cancer CenterMolecular Therapeutics Program, Fox Chase Cancer CenterAbstract Non-small cell lung cancer (NSCLC) has limited treatment options. Expression of the RNA-binding protein (RBP) Musashi-2 (MSI2) is elevated in a subset of non-small cell lung cancer (NSCLC) tumors upon progression, and drives NSCLC metastasis. We evaluated the mechanism of MSI2 action in NSCLC to gain therapeutically useful insights. Reverse phase protein array (RPPA) analysis of MSI2-depleted versus control Kras LA1/+ ; Trp53 R172HΔG/+ NSCLC cell lines identified EGFR as a MSI2-regulated protein. MSI2 control of EGFR expression and activity in an NSCLC cell line panel was studied using RT-PCR, Western blots, and RNA immunoprecipitation. Functional consequences of MSI2 depletion were explored for cell growth and response to EGFR-targeting drugs, in vitro and in vivo. Expression relationships were validated using human tissue microarrays. MSI2 depletion significantly reduced EGFR protein expression, phosphorylation, or both. Comparison of protein and mRNA expression indicated a post-transcriptional activity of MSI2 in control of steady state levels of EGFR. RNA immunoprecipitation analysis demonstrated that MSI2 directly binds to EGFR mRNA, and sequence analysis predicted MSI2 binding sites in the murine and human EGFR mRNAs. MSI2 depletion selectively impaired cell proliferation in NSCLC cell lines with activating mutations of EGFR (EGFRmut). Further, depletion of MSI2 in combination with EGFR inhibitors such as erlotinib, afatinib, and osimertinib selectively reduced the growth of EGFRmut NSCLC cells and xenografts. EGFR and MSI2 were significantly co-expressed in EGFRmut human NSCLCs. These results define MSI2 as a direct regulator of EGFR protein expression, and suggest inhibition of MSI2 could be of clinical value in EGFRmut NSCLC.https://doi.org/10.1038/s41389-021-00317-y |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Petr Makhov Igor Bychkov Bulat Faezov Alexander Deneka Alexander Kudinov Emmanuelle Nicolas Rohan Brebion Eleanor Avril Kathy Q. Cai Leonid V. Kharin Mark Voloshin Elena Frantsiyants Nikolay Karnaukhov Oleg I. Kit Iuliia Topchu Rushaniya Fazliyeva Anna S. Nikonova Ilya G. Serebriiskii Hossein Borghaei Martin Edelman Essel Dulaimi Erica A. Golemis Yanis Boumber |
spellingShingle |
Petr Makhov Igor Bychkov Bulat Faezov Alexander Deneka Alexander Kudinov Emmanuelle Nicolas Rohan Brebion Eleanor Avril Kathy Q. Cai Leonid V. Kharin Mark Voloshin Elena Frantsiyants Nikolay Karnaukhov Oleg I. Kit Iuliia Topchu Rushaniya Fazliyeva Anna S. Nikonova Ilya G. Serebriiskii Hossein Borghaei Martin Edelman Essel Dulaimi Erica A. Golemis Yanis Boumber Musashi-2 (MSI2) regulates epidermal growth factor receptor (EGFR) expression and response to EGFR inhibitors in EGFR-mutated non-small cell lung cancer (NSCLC) Oncogenesis |
author_facet |
Petr Makhov Igor Bychkov Bulat Faezov Alexander Deneka Alexander Kudinov Emmanuelle Nicolas Rohan Brebion Eleanor Avril Kathy Q. Cai Leonid V. Kharin Mark Voloshin Elena Frantsiyants Nikolay Karnaukhov Oleg I. Kit Iuliia Topchu Rushaniya Fazliyeva Anna S. Nikonova Ilya G. Serebriiskii Hossein Borghaei Martin Edelman Essel Dulaimi Erica A. Golemis Yanis Boumber |
author_sort |
Petr Makhov |
title |
Musashi-2 (MSI2) regulates epidermal growth factor receptor (EGFR) expression and response to EGFR inhibitors in EGFR-mutated non-small cell lung cancer (NSCLC) |
title_short |
Musashi-2 (MSI2) regulates epidermal growth factor receptor (EGFR) expression and response to EGFR inhibitors in EGFR-mutated non-small cell lung cancer (NSCLC) |
title_full |
Musashi-2 (MSI2) regulates epidermal growth factor receptor (EGFR) expression and response to EGFR inhibitors in EGFR-mutated non-small cell lung cancer (NSCLC) |
title_fullStr |
Musashi-2 (MSI2) regulates epidermal growth factor receptor (EGFR) expression and response to EGFR inhibitors in EGFR-mutated non-small cell lung cancer (NSCLC) |
title_full_unstemmed |
Musashi-2 (MSI2) regulates epidermal growth factor receptor (EGFR) expression and response to EGFR inhibitors in EGFR-mutated non-small cell lung cancer (NSCLC) |
title_sort |
musashi-2 (msi2) regulates epidermal growth factor receptor (egfr) expression and response to egfr inhibitors in egfr-mutated non-small cell lung cancer (nsclc) |
publisher |
Nature Publishing Group |
series |
Oncogenesis |
issn |
2157-9024 |
publishDate |
2021-03-01 |
description |
Abstract Non-small cell lung cancer (NSCLC) has limited treatment options. Expression of the RNA-binding protein (RBP) Musashi-2 (MSI2) is elevated in a subset of non-small cell lung cancer (NSCLC) tumors upon progression, and drives NSCLC metastasis. We evaluated the mechanism of MSI2 action in NSCLC to gain therapeutically useful insights. Reverse phase protein array (RPPA) analysis of MSI2-depleted versus control Kras LA1/+ ; Trp53 R172HΔG/+ NSCLC cell lines identified EGFR as a MSI2-regulated protein. MSI2 control of EGFR expression and activity in an NSCLC cell line panel was studied using RT-PCR, Western blots, and RNA immunoprecipitation. Functional consequences of MSI2 depletion were explored for cell growth and response to EGFR-targeting drugs, in vitro and in vivo. Expression relationships were validated using human tissue microarrays. MSI2 depletion significantly reduced EGFR protein expression, phosphorylation, or both. Comparison of protein and mRNA expression indicated a post-transcriptional activity of MSI2 in control of steady state levels of EGFR. RNA immunoprecipitation analysis demonstrated that MSI2 directly binds to EGFR mRNA, and sequence analysis predicted MSI2 binding sites in the murine and human EGFR mRNAs. MSI2 depletion selectively impaired cell proliferation in NSCLC cell lines with activating mutations of EGFR (EGFRmut). Further, depletion of MSI2 in combination with EGFR inhibitors such as erlotinib, afatinib, and osimertinib selectively reduced the growth of EGFRmut NSCLC cells and xenografts. EGFR and MSI2 were significantly co-expressed in EGFRmut human NSCLCs. These results define MSI2 as a direct regulator of EGFR protein expression, and suggest inhibition of MSI2 could be of clinical value in EGFRmut NSCLC. |
url |
https://doi.org/10.1038/s41389-021-00317-y |
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