Systematic Analysis of Genetic and Pathway Determinants of Eribulin Sensitivity across 100 Human Cancer Cell Lines from the Cancer Cell Line Encyclopedia (CCLE)
Eribulin, a natural product-based microtubule targeting agent with cytotoxic and noncytotoxic mechanisms, is FDA approved for certain patients with advanced breast cancer and liposarcoma. To investigate the feasibility of developing drug-specific predictive biomarkers, we quantified antiproliferativ...
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MDPI AG
2022-09-01
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Series: | Cancers |
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Online Access: | https://www.mdpi.com/2072-6694/14/18/4532 |
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author | Pallavi Sachdev Roy Ronen Janusz Dutkowski Bruce A. Littlefield |
author_facet | Pallavi Sachdev Roy Ronen Janusz Dutkowski Bruce A. Littlefield |
author_sort | Pallavi Sachdev |
collection | DOAJ |
description | Eribulin, a natural product-based microtubule targeting agent with cytotoxic and noncytotoxic mechanisms, is FDA approved for certain patients with advanced breast cancer and liposarcoma. To investigate the feasibility of developing drug-specific predictive biomarkers, we quantified antiproliferative activities of eribulin versus paclitaxel and vinorelbine against 100 human cancer cell lines from the Cancer Cell Line Encyclopedia, and correlated results with publicly available databases to identify genes and pathways associated with eribulin response, either uniquely or shared with paclitaxel or vinorelbine. Mean expression ratios of 11,985 genes between the most and least sensitive cell line quartiles were sorted by <i>p</i>-values and drug overlaps, yielding 52, 29 and 80 genes uniquely associated with eribulin, paclitaxel and vinorelbine, respectively. Further restriction to minimum 2-fold ratios followed by reintroducing data from the middle two quartiles identified 9 and 13 drug-specific unique fingerprint genes for eribulin and vinorelbine, respectively; surprisingly, no gene met all criteria for paclitaxel. Interactome and Reactome pathway analyses showed that unique fingerprint genes of both drugs were primarily associated with cellular signaling, not microtubule-related pathways, although considerable differences existed in individual pathways identified. Finally, four-gene (<i>C5ORF38</i>, <i>DAAM1</i>, <i>IRX2</i>, <i>CD70</i>) and five-gene (<i>EPHA2</i>, <i>NGEF</i>, <i>SEPTIN10</i>, <i>TRIP10</i>, <i>VSIG10</i>) multivariate regression models for eribulin and vinorelbine showed high statistical correlation with drug-specific responses across the 100 cell lines and accurately calculated predicted mean IC50s for the most and least sensitive cell line quartiles as surrogates for responders and nonresponders, respectively. Collectively, these results provide a foundation for developing drug-specific predictive biomarkers for eribulin and vinorelbine. |
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issn | 2072-6694 |
language | English |
last_indexed | 2024-03-10T00:28:13Z |
publishDate | 2022-09-01 |
publisher | MDPI AG |
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series | Cancers |
spelling | doaj.art-05213d6000aa48cd8647a3efd2c043db2023-11-23T15:28:54ZengMDPI AGCancers2072-66942022-09-011418453210.3390/cancers14184532Systematic Analysis of Genetic and Pathway Determinants of Eribulin Sensitivity across 100 Human Cancer Cell Lines from the Cancer Cell Line Encyclopedia (CCLE)Pallavi Sachdev0Roy Ronen1Janusz Dutkowski2Bruce A. Littlefield3Eisai Inc., Nutley, NJ 07110, USAData4Cure Inc., La Jolla, CA 92037, USAData4Cure Inc., La Jolla, CA 92037, USAEisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USAEribulin, a natural product-based microtubule targeting agent with cytotoxic and noncytotoxic mechanisms, is FDA approved for certain patients with advanced breast cancer and liposarcoma. To investigate the feasibility of developing drug-specific predictive biomarkers, we quantified antiproliferative activities of eribulin versus paclitaxel and vinorelbine against 100 human cancer cell lines from the Cancer Cell Line Encyclopedia, and correlated results with publicly available databases to identify genes and pathways associated with eribulin response, either uniquely or shared with paclitaxel or vinorelbine. Mean expression ratios of 11,985 genes between the most and least sensitive cell line quartiles were sorted by <i>p</i>-values and drug overlaps, yielding 52, 29 and 80 genes uniquely associated with eribulin, paclitaxel and vinorelbine, respectively. Further restriction to minimum 2-fold ratios followed by reintroducing data from the middle two quartiles identified 9 and 13 drug-specific unique fingerprint genes for eribulin and vinorelbine, respectively; surprisingly, no gene met all criteria for paclitaxel. Interactome and Reactome pathway analyses showed that unique fingerprint genes of both drugs were primarily associated with cellular signaling, not microtubule-related pathways, although considerable differences existed in individual pathways identified. Finally, four-gene (<i>C5ORF38</i>, <i>DAAM1</i>, <i>IRX2</i>, <i>CD70</i>) and five-gene (<i>EPHA2</i>, <i>NGEF</i>, <i>SEPTIN10</i>, <i>TRIP10</i>, <i>VSIG10</i>) multivariate regression models for eribulin and vinorelbine showed high statistical correlation with drug-specific responses across the 100 cell lines and accurately calculated predicted mean IC50s for the most and least sensitive cell line quartiles as surrogates for responders and nonresponders, respectively. Collectively, these results provide a foundation for developing drug-specific predictive biomarkers for eribulin and vinorelbine.https://www.mdpi.com/2072-6694/14/18/4532eribulinpaclitaxelvinorelbinegene expressionpredictive biomarkers |
spellingShingle | Pallavi Sachdev Roy Ronen Janusz Dutkowski Bruce A. Littlefield Systematic Analysis of Genetic and Pathway Determinants of Eribulin Sensitivity across 100 Human Cancer Cell Lines from the Cancer Cell Line Encyclopedia (CCLE) Cancers eribulin paclitaxel vinorelbine gene expression predictive biomarkers |
title | Systematic Analysis of Genetic and Pathway Determinants of Eribulin Sensitivity across 100 Human Cancer Cell Lines from the Cancer Cell Line Encyclopedia (CCLE) |
title_full | Systematic Analysis of Genetic and Pathway Determinants of Eribulin Sensitivity across 100 Human Cancer Cell Lines from the Cancer Cell Line Encyclopedia (CCLE) |
title_fullStr | Systematic Analysis of Genetic and Pathway Determinants of Eribulin Sensitivity across 100 Human Cancer Cell Lines from the Cancer Cell Line Encyclopedia (CCLE) |
title_full_unstemmed | Systematic Analysis of Genetic and Pathway Determinants of Eribulin Sensitivity across 100 Human Cancer Cell Lines from the Cancer Cell Line Encyclopedia (CCLE) |
title_short | Systematic Analysis of Genetic and Pathway Determinants of Eribulin Sensitivity across 100 Human Cancer Cell Lines from the Cancer Cell Line Encyclopedia (CCLE) |
title_sort | systematic analysis of genetic and pathway determinants of eribulin sensitivity across 100 human cancer cell lines from the cancer cell line encyclopedia ccle |
topic | eribulin paclitaxel vinorelbine gene expression predictive biomarkers |
url | https://www.mdpi.com/2072-6694/14/18/4532 |
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