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Published on: May 13, 2015
MEK inhibitor cobimetinib rescues a dRaf mutant lethal phenotype in Drosophila melanogaster
Isabelle Pfeifle1, Jens Bohnekamp2,3, Anna Volkhardt1
1Department of Dermatology, Venereology and Allergology, University of Leipzig, Leipzig, Germany.
Abstract:
Since Drosophila melanogaster has proven to be a useful model system to study phenotypes of oncogenic mutations and to identify new anti-cancer drugs, we generated human BRAFV600E homologous dRaf mutant (dRafA572E ) Drosophila melanogaster strains to use these for characterisation of mutant phenotypes and exploit these phenotypes for drug testing. For mutant gene expression, the GAL4/UAS expression system was used. dRafA572E was expressed tissue-specific in the eye, epidermis, heart, wings, secretory glands and in the whole animal. Expression of dRaf A572E under the control of an eye-specific driver led to semi-lethality and a rough eye phenotype. The vast majority of other tissue-specific and ubiquitous drivers led to a lethal phenotype only. The rough eye phenotype was used to test BRAF inhibitor vemurafenib and MEK1/2 inhibitor cobimetinib. There was no phenotype rescue by this treatment. However, a significant rescue of the lethal phenotype was observed under a gut-specific driver. Here, MEK1/2 inhibitor cobimetinib rescued Drosophila larvae to reach pupal stage in 37% of cases as compared to 1% in control experiments. Taken together, the BRAFV600E homolog dRaf A572E exerts mostly lethal effects in Drosophila. Gut-specific dRaf A572E expression might in future be developed further for drug testing.
Insights
Researchers created BRAFV600E homologous mutant Drosophila melanogaster strains to study cancer phenotypes and test anti-cancer drugs. A gut-specific BRAF homolog mutant showed significant rescue with MEK1/2 inhibitor cobimetinib, indicating potential for drug testing.
Area of Science:
- Genetics and Genomics
- Developmental Biology
- Pharmacology
Background:
- Drosophila melanogaster is a valuable model for studying oncogenic mutations and discovering anti-cancer drugs.
- The BRAFV600E mutation is a key driver in various human cancers.
- Developing homologous mutant models in Drosophila can facilitate cancer research and drug screening.
Purpose of the Study:
- To generate and characterize Drosophila melanogaster strains expressing a human BRAFV600E homolog (dRafA572E).
- To investigate the phenotypic effects of tissue-specific dRafA572E expression.
- To evaluate the efficacy of BRAF and MEK inhibitors in rescuing mutant phenotypes for potential drug testing.
Main Methods:
- Generation of dRafA572E mutant Drosophila melanogaster strains using the GAL4/UAS system.
- Tissue-specific expression of dRafA572E in various organs (eye, epidermis, heart, wings, glands) and ubiquitously.
- Phenotypic characterization including semi-lethality and rough eye phenotypes.
- Drug screening using BRAF inhibitor vemurafenib and MEK1/2 inhibitor cobimetinib.
Main Results:
- Expression of dRafA572E in the eye caused semi-lethality and a rough eye phenotype.
- Most other tissue-specific and ubiquitous expressions resulted in lethal phenotypes.
- BRAF inhibitor vemurafenib and MEK1/2 inhibitor cobimetinib did not rescue the eye phenotype.
- MEK1/2 inhibitor cobimetinib significantly rescued the lethal phenotype in gut-specific expression, increasing survival to the pupal stage.
Conclusions:
- The BRAFV600E homolog dRafA572E primarily induces lethal effects in Drosophila.
- Gut-specific expression of dRafA572E in Drosophila offers a promising model for anti-cancer drug testing.
- MEK1/2 inhibition demonstrates therapeutic potential against BRAF-mutant phenotypes in this model system.
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