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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Main Authors: Pallavi Sachdev, Roy Ronen, Janusz Dutkowski, Bruce A. Littlefield
Format: Article
Language:English
Published: MDPI AG 2022-09-01
Series:Cancers
Subjects:
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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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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