An EGFR-induced Drosophila lung tumor model identifies alternative combination treatments
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An EGFR-induced Drosophila lung tumor model identifies alternative combination treatments. / Bossen, Judith; Uliczka, Karin; Steen, Line; Pfefferkorn, Roxana; Mai, Mandy Mong-Quyen; Burkhardt, Lia; Spohn, Michael; Bruchhaus, Iris; Fink, Christine; Heine, Holger; Roeder, Thomas.
In: MOL CANCER THER, Vol. 18, No. 9, 09.2019, p. 1659-1668.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - An EGFR-induced Drosophila lung tumor model identifies alternative combination treatments
AU - Bossen, Judith
AU - Uliczka, Karin
AU - Steen, Line
AU - Pfefferkorn, Roxana
AU - Mai, Mandy Mong-Quyen
AU - Burkhardt, Lia
AU - Spohn, Michael
AU - Bruchhaus, Iris
AU - Fink, Christine
AU - Heine, Holger
AU - Roeder, Thomas
N1 - Copyright ©2019, American Association for Cancer Research.
PY - 2019/9
Y1 - 2019/9
N2 - 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.
AB - 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.
U2 - 10.1158/1535-7163.MCT-19-0168
DO - 10.1158/1535-7163.MCT-19-0168
M3 - SCORING: Journal article
C2 - 31217165
VL - 18
SP - 1659
EP - 1668
JO - MOL CANCER THER
JF - MOL CANCER THER
SN - 1535-7163
IS - 9
ER -
