Growth factor signaling predicts therapy resistance mechanisms and defines neuroblastoma subtypes
Neuroblastoma (NB) has a low frequency of recurrent mutations compared to other cancers, which hinders the development of targeted therapies and novel risk stratification strategies. Multikinase inhibitors have shown potential in treating high-risk NB, but their efficacy is likely impaired by the ca...
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| Veröffentlicht in: | Oncogene 2021-11, Vol.40 (44), p.6258-6272 |
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| creator | Lebedev, Timofey Vagapova, Elmira Spirin, Pavel Rubtsov, Petr Astashkova, Olga Mikheeva, Alesya Sorokin, Maxim Vladimirova, Uliana Suntsova, Maria Konovalov, Dmitry Roumiantsev, Alexander Stocking, Carol Buzdin, Anton Prassolov, Vladimir |
| description | Neuroblastoma (NB) has a low frequency of recurrent mutations compared to other cancers, which hinders the development of targeted therapies and novel risk stratification strategies. Multikinase inhibitors have shown potential in treating high-risk NB, but their efficacy is likely impaired by the cancer cells’ ability to adapt to these drugs through the employment of alternative signaling pathways. Based on the expression of 48 growth factor-related genes in 1189 NB tumors, we have developed a model for NB patient survival prediction. This model discriminates between stage 4 NB tumors with favorable outcomes (>80% overall survival) and very poor outcomes ( |
| doi_str_mv | 10.1038/s41388-021-02018-7 |
| format | Article |
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Multikinase inhibitors have shown potential in treating high-risk NB, but their efficacy is likely impaired by the cancer cells’ ability to adapt to these drugs through the employment of alternative signaling pathways. Based on the expression of 48 growth factor-related genes in 1189 NB tumors, we have developed a model for NB patient survival prediction. This model discriminates between stage 4 NB tumors with favorable outcomes (>80% overall survival) and very poor outcomes (<10%) independently from MYCN-amplification status. Using signaling pathway analysis and gene set enrichment methods in 60 NB patients with known therapy response, we identified signaling pathways, including EPO, NGF, and HGF, upregulated in patients with no or partial response. In a therapeutic setting, we showed that among six selected growth factors, EPO, and NGF showed the most pronounced protective effects in vitro against several promising anti-NB multikinase inhibitors: imatinib, dasatinib, crizotinib, cabozantinib, and axitinib. Mechanistically kinase inhibitors potentiated NB cells to stronger ERK activation by EPO and NGF. The protective action of these growth factors strongly correlated with ERK activation and was ERK-dependent. ERK inhibitors combined with anticancer drugs, especially with dasatinib, showed a synergistic effect on NB cell death. Consideration of growth factor signaling activity benefits NB outcome prediction and tailoring therapy regimens to treat NB.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/s41388-021-02018-7</identifier><identifier>PMID: 34556815</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/21 ; 13/31 ; 13/95 ; 14/10 ; 38/39 ; 631/67/2332 ; 631/67/69 ; Analysis ; Antimitotic agents ; Antineoplastic agents ; Antineoplastic drugs ; Antitumor agents ; Apoptosis ; Cancer ; Care and treatment ; Cell activation ; Cell Biology ; Cell death ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Diagnosis ; Dosage and administration ; Drug Resistance, Neoplasm ; Erythropoietin - genetics ; Extracellular signal-regulated kinase ; Gene Expression Regulation, Neoplastic - drug effects ; Growth factors ; Health aspects ; Human Genetics ; Humans ; Imatinib ; Internal Medicine ; Kinases ; Medicine ; Medicine & Public Health ; Mutation ; Neoplasm Staging ; Nerve growth factor ; Nerve Growth Factor - genetics ; Neuroblastoma ; Neuroblastoma - drug therapy ; Neuroblastoma - genetics ; Neuroblastoma - pathology ; Observations ; Oncology ; Patients ; Protein Kinase Inhibitors - pharmacology ; Relapse ; Risk factors ; Signal transduction ; Signal Transduction - drug effects ; Survival Analysis ; Tumors</subject><ispartof>Oncogene, 2021-11, Vol.40 (44), p.6258-6272</ispartof><rights>The Author(s) 2021</rights><rights>2021. The Author(s).</rights><rights>COPYRIGHT 2021 Nature Publishing Group</rights><rights>The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c541t-27892b762bf10452ee9a4e2e121a21c4ba33510b45621466f711db16be0307a73</citedby><cites>FETCH-LOGICAL-c541t-27892b762bf10452ee9a4e2e121a21c4ba33510b45621466f711db16be0307a73</cites><orcidid>0000-0002-5966-0914 ; 0000-0002-2680-9356</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41388-021-02018-7$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41388-021-02018-7$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34556815$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lebedev, Timofey</creatorcontrib><creatorcontrib>Vagapova, Elmira</creatorcontrib><creatorcontrib>Spirin, Pavel</creatorcontrib><creatorcontrib>Rubtsov, Petr</creatorcontrib><creatorcontrib>Astashkova, Olga</creatorcontrib><creatorcontrib>Mikheeva, Alesya</creatorcontrib><creatorcontrib>Sorokin, Maxim</creatorcontrib><creatorcontrib>Vladimirova, Uliana</creatorcontrib><creatorcontrib>Suntsova, Maria</creatorcontrib><creatorcontrib>Konovalov, Dmitry</creatorcontrib><creatorcontrib>Roumiantsev, Alexander</creatorcontrib><creatorcontrib>Stocking, Carol</creatorcontrib><creatorcontrib>Buzdin, Anton</creatorcontrib><creatorcontrib>Prassolov, Vladimir</creatorcontrib><title>Growth factor signaling predicts therapy resistance mechanisms and defines neuroblastoma subtypes</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Neuroblastoma (NB) has a low frequency of recurrent mutations compared to other cancers, which hinders the development of targeted therapies and novel risk stratification strategies. Multikinase inhibitors have shown potential in treating high-risk NB, but their efficacy is likely impaired by the cancer cells’ ability to adapt to these drugs through the employment of alternative signaling pathways. Based on the expression of 48 growth factor-related genes in 1189 NB tumors, we have developed a model for NB patient survival prediction. This model discriminates between stage 4 NB tumors with favorable outcomes (>80% overall survival) and very poor outcomes (<10%) independently from MYCN-amplification status. Using signaling pathway analysis and gene set enrichment methods in 60 NB patients with known therapy response, we identified signaling pathways, including EPO, NGF, and HGF, upregulated in patients with no or partial response. 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Consideration of growth factor signaling activity benefits NB outcome prediction and tailoring therapy regimens to treat NB.</description><subject>13/21</subject><subject>13/31</subject><subject>13/95</subject><subject>14/10</subject><subject>38/39</subject><subject>631/67/2332</subject><subject>631/67/69</subject><subject>Analysis</subject><subject>Antimitotic agents</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic drugs</subject><subject>Antitumor agents</subject><subject>Apoptosis</subject><subject>Cancer</subject><subject>Care and treatment</subject><subject>Cell activation</subject><subject>Cell Biology</subject><subject>Cell death</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Diagnosis</subject><subject>Dosage and administration</subject><subject>Drug Resistance, Neoplasm</subject><subject>Erythropoietin - genetics</subject><subject>Extracellular signal-regulated kinase</subject><subject>Gene Expression Regulation, Neoplastic - 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Multikinase inhibitors have shown potential in treating high-risk NB, but their efficacy is likely impaired by the cancer cells’ ability to adapt to these drugs through the employment of alternative signaling pathways. Based on the expression of 48 growth factor-related genes in 1189 NB tumors, we have developed a model for NB patient survival prediction. This model discriminates between stage 4 NB tumors with favorable outcomes (>80% overall survival) and very poor outcomes (<10%) independently from MYCN-amplification status. Using signaling pathway analysis and gene set enrichment methods in 60 NB patients with known therapy response, we identified signaling pathways, including EPO, NGF, and HGF, upregulated in patients with no or partial response. In a therapeutic setting, we showed that among six selected growth factors, EPO, and NGF showed the most pronounced protective effects in vitro against several promising anti-NB multikinase inhibitors: imatinib, dasatinib, crizotinib, cabozantinib, and axitinib. Mechanistically kinase inhibitors potentiated NB cells to stronger ERK activation by EPO and NGF. The protective action of these growth factors strongly correlated with ERK activation and was ERK-dependent. ERK inhibitors combined with anticancer drugs, especially with dasatinib, showed a synergistic effect on NB cell death. Consideration of growth factor signaling activity benefits NB outcome prediction and tailoring therapy regimens to treat NB.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34556815</pmid><doi>10.1038/s41388-021-02018-7</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-5966-0914</orcidid><orcidid>https://orcid.org/0000-0002-2680-9356</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 13/21 13/31 13/95 14/10 38/39 631/67/2332 631/67/69 Analysis Antimitotic agents Antineoplastic agents Antineoplastic drugs Antitumor agents Apoptosis Cancer Care and treatment Cell activation Cell Biology Cell death Cell Line, Tumor Cell Proliferation - drug effects Cell Survival - drug effects Diagnosis Dosage and administration Drug Resistance, Neoplasm Erythropoietin - genetics Extracellular signal-regulated kinase Gene Expression Regulation, Neoplastic - drug effects Growth factors Health aspects Human Genetics Humans Imatinib Internal Medicine Kinases Medicine Medicine & Public Health Mutation Neoplasm Staging Nerve growth factor Nerve Growth Factor - genetics Neuroblastoma Neuroblastoma - drug therapy Neuroblastoma - genetics Neuroblastoma - pathology Observations Oncology Patients Protein Kinase Inhibitors - pharmacology Relapse Risk factors Signal transduction Signal Transduction - drug effects Survival Analysis Tumors |
| title | Growth factor signaling predicts therapy resistance mechanisms and defines neuroblastoma subtypes |
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