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An EGFR-Induced Drosophila Lung Tumor Model Identifies Alternative Combination Treatments
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| Zeitschriftentitel: | Molecular Cancer Therapeutics |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , |
| In: | Molecular Cancer Therapeutics, 18, 2019, 9, S. 1659-1668 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Association for Cancer Research (AACR)
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| Schlagwörter: |
| author_facet |
Bossen, Judith Uliczka, Karin Steen, Line Pfefferkorn, Roxana Mai, Mandy Mong-Quyen Burkhardt, Lia Spohn, Michael Bruchhaus, Iris Fink, Christine Heine, Holger Roeder, Thomas Bossen, Judith Uliczka, Karin Steen, Line Pfefferkorn, Roxana Mai, Mandy Mong-Quyen Burkhardt, Lia Spohn, Michael Bruchhaus, Iris Fink, Christine Heine, Holger Roeder, Thomas |
|---|---|
| author |
Bossen, Judith Uliczka, Karin Steen, Line Pfefferkorn, Roxana Mai, Mandy Mong-Quyen Burkhardt, Lia Spohn, Michael Bruchhaus, Iris Fink, Christine Heine, Holger Roeder, Thomas |
| spellingShingle |
Bossen, Judith Uliczka, Karin Steen, Line Pfefferkorn, Roxana Mai, Mandy Mong-Quyen Burkhardt, Lia Spohn, Michael Bruchhaus, Iris Fink, Christine Heine, Holger Roeder, Thomas Molecular Cancer Therapeutics An EGFR-Induced Drosophila Lung Tumor Model Identifies Alternative Combination Treatments Cancer Research Oncology |
| author_sort |
bossen, judith |
| spelling |
Bossen, Judith Uliczka, Karin Steen, Line Pfefferkorn, Roxana Mai, Mandy Mong-Quyen Burkhardt, Lia Spohn, Michael Bruchhaus, Iris Fink, Christine Heine, Holger Roeder, Thomas 1535-7163 1538-8514 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1535-7163.mct-19-0168 <jats:title>Abstract</jats:title> <jats:p>Lung cancer is the leading cause of cancer-associated mortality. Mutations in the EGFR gene are among the most important inducers of lung tumor development, but success of personalized therapies is still limited because of toxicity or developing resistances. We expressed constitutively active EGFR (EGFRCA) exclusively in the airway system of Drosophila melanogaster and performed comprehensive phenotyping. Ectopic expression of EGFRCA induced massive hyper- and metaplasia, leading to early death. We used the lethal phenotype as a readout and screened a library of FDA-approved compounds and found that among the 1,000 compounds, only the tyrosine kinase inhibitors (TKI) afatinib, gefitinib, and ibrutinib rescued lethality in a whole-animal screening approach. Furthermore, we screened the library in the presence of a subtherapeutic afatinib dose and identified bazedoxifene as a synergistically acting compound that rescues EGFR-induced lethality. Our findings highlight the potential of Drosophila-based whole-animal screening approaches not only to identify specific EGFR inhibitors but also to discover compounds that act synergistically with known TKIs. Moreover, we showed that targeting the EGFR together with STAT-signaling is a promising strategy for lung tumor treatment.</jats:p> An EGFR-Induced <i>Drosophila</i> Lung Tumor Model Identifies Alternative Combination Treatments Molecular Cancer Therapeutics |
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| title |
An EGFR-Induced Drosophila Lung Tumor Model Identifies Alternative Combination Treatments |
| title_unstemmed |
An EGFR-Induced Drosophila Lung Tumor Model Identifies Alternative Combination Treatments |
| title_full |
An EGFR-Induced Drosophila Lung Tumor Model Identifies Alternative Combination Treatments |
| title_fullStr |
An EGFR-Induced Drosophila Lung Tumor Model Identifies Alternative Combination Treatments |
| title_full_unstemmed |
An EGFR-Induced Drosophila Lung Tumor Model Identifies Alternative Combination Treatments |
| title_short |
An EGFR-Induced Drosophila Lung Tumor Model Identifies Alternative Combination Treatments |
| title_sort |
an egfr-induced <i>drosophila</i> lung tumor model identifies alternative combination treatments |
| topic |
Cancer Research Oncology |
| url |
http://dx.doi.org/10.1158/1535-7163.mct-19-0168 |
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2019 |
| physical |
1659-1668 |
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<jats:title>Abstract</jats:title>
<jats:p>Lung cancer is the leading cause of cancer-associated mortality. Mutations in the EGFR gene are among the most important inducers of lung tumor development, but success of personalized therapies is still limited because of toxicity or developing resistances. We expressed constitutively active EGFR (EGFRCA) exclusively in the airway system of Drosophila melanogaster and performed comprehensive phenotyping. Ectopic expression of EGFRCA induced massive hyper- and metaplasia, leading to early death. We used the lethal phenotype as a readout and screened a library of FDA-approved compounds and found that among the 1,000 compounds, only the tyrosine kinase inhibitors (TKI) afatinib, gefitinib, and ibrutinib rescued lethality in a whole-animal screening approach. Furthermore, we screened the library in the presence of a subtherapeutic afatinib dose and identified bazedoxifene as a synergistically acting compound that rescues EGFR-induced lethality. Our findings highlight the potential of Drosophila-based whole-animal screening approaches not only to identify specific EGFR inhibitors but also to discover compounds that act synergistically with known TKIs. Moreover, we showed that targeting the EGFR together with STAT-signaling is a promising strategy for lung tumor treatment.</jats:p> |
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| author | Bossen, Judith, Uliczka, Karin, Steen, Line, Pfefferkorn, Roxana, Mai, Mandy Mong-Quyen, Burkhardt, Lia, Spohn, Michael, Bruchhaus, Iris, Fink, Christine, Heine, Holger, Roeder, Thomas |
| author_facet | Bossen, Judith, Uliczka, Karin, Steen, Line, Pfefferkorn, Roxana, Mai, Mandy Mong-Quyen, Burkhardt, Lia, Spohn, Michael, Bruchhaus, Iris, Fink, Christine, Heine, Holger, Roeder, Thomas, Bossen, Judith, Uliczka, Karin, Steen, Line, Pfefferkorn, Roxana, Mai, Mandy Mong-Quyen, Burkhardt, Lia, Spohn, Michael, Bruchhaus, Iris, Fink, Christine, Heine, Holger, Roeder, Thomas |
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| description | <jats:title>Abstract</jats:title> <jats:p>Lung cancer is the leading cause of cancer-associated mortality. Mutations in the EGFR gene are among the most important inducers of lung tumor development, but success of personalized therapies is still limited because of toxicity or developing resistances. We expressed constitutively active EGFR (EGFRCA) exclusively in the airway system of Drosophila melanogaster and performed comprehensive phenotyping. Ectopic expression of EGFRCA induced massive hyper- and metaplasia, leading to early death. We used the lethal phenotype as a readout and screened a library of FDA-approved compounds and found that among the 1,000 compounds, only the tyrosine kinase inhibitors (TKI) afatinib, gefitinib, and ibrutinib rescued lethality in a whole-animal screening approach. Furthermore, we screened the library in the presence of a subtherapeutic afatinib dose and identified bazedoxifene as a synergistically acting compound that rescues EGFR-induced lethality. Our findings highlight the potential of Drosophila-based whole-animal screening approaches not only to identify specific EGFR inhibitors but also to discover compounds that act synergistically with known TKIs. Moreover, we showed that targeting the EGFR together with STAT-signaling is a promising strategy for lung tumor treatment.</jats:p> |
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| imprint_str_mv | American Association for Cancer Research (AACR), 2019 |
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| spelling | Bossen, Judith Uliczka, Karin Steen, Line Pfefferkorn, Roxana Mai, Mandy Mong-Quyen Burkhardt, Lia Spohn, Michael Bruchhaus, Iris Fink, Christine Heine, Holger Roeder, Thomas 1535-7163 1538-8514 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1535-7163.mct-19-0168 <jats:title>Abstract</jats:title> <jats:p>Lung cancer is the leading cause of cancer-associated mortality. Mutations in the EGFR gene are among the most important inducers of lung tumor development, but success of personalized therapies is still limited because of toxicity or developing resistances. We expressed constitutively active EGFR (EGFRCA) exclusively in the airway system of Drosophila melanogaster and performed comprehensive phenotyping. Ectopic expression of EGFRCA induced massive hyper- and metaplasia, leading to early death. We used the lethal phenotype as a readout and screened a library of FDA-approved compounds and found that among the 1,000 compounds, only the tyrosine kinase inhibitors (TKI) afatinib, gefitinib, and ibrutinib rescued lethality in a whole-animal screening approach. Furthermore, we screened the library in the presence of a subtherapeutic afatinib dose and identified bazedoxifene as a synergistically acting compound that rescues EGFR-induced lethality. Our findings highlight the potential of Drosophila-based whole-animal screening approaches not only to identify specific EGFR inhibitors but also to discover compounds that act synergistically with known TKIs. Moreover, we showed that targeting the EGFR together with STAT-signaling is a promising strategy for lung tumor treatment.</jats:p> An EGFR-Induced <i>Drosophila</i> Lung Tumor Model Identifies Alternative Combination Treatments Molecular Cancer Therapeutics |
| spellingShingle | Bossen, Judith, Uliczka, Karin, Steen, Line, Pfefferkorn, Roxana, Mai, Mandy Mong-Quyen, Burkhardt, Lia, Spohn, Michael, Bruchhaus, Iris, Fink, Christine, Heine, Holger, Roeder, Thomas, Molecular Cancer Therapeutics, An EGFR-Induced Drosophila Lung Tumor Model Identifies Alternative Combination Treatments, Cancer Research, Oncology |
| title | An EGFR-Induced Drosophila Lung Tumor Model Identifies Alternative Combination Treatments |
| title_full | An EGFR-Induced Drosophila Lung Tumor Model Identifies Alternative Combination Treatments |
| title_fullStr | An EGFR-Induced Drosophila Lung Tumor Model Identifies Alternative Combination Treatments |
| title_full_unstemmed | An EGFR-Induced Drosophila Lung Tumor Model Identifies Alternative Combination Treatments |
| title_short | An EGFR-Induced Drosophila Lung Tumor Model Identifies Alternative Combination Treatments |
| title_sort | an egfr-induced <i>drosophila</i> lung tumor model identifies alternative combination treatments |
| title_unstemmed | An EGFR-Induced Drosophila Lung Tumor Model Identifies Alternative Combination Treatments |
| topic | Cancer Research, Oncology |
| url | http://dx.doi.org/10.1158/1535-7163.mct-19-0168 |