Drosophila RASopathy models identify disease subtype differences and biomarkers of drug efficacy
Tirtha K. Das,
Jared Gatto,
Rupa Mirmira,
Ethan Hourizadeh,
Dalia Kaufman,
Bruce D. Gelb,
Ross Cagan
Affiliations
Tirtha K. Das
Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York NY, USA; The Mindich Child Health and Development Institute, Department of Pediatrics, Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York NY, USA
Jared Gatto
Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York NY, USA; The Mindich Child Health and Development Institute, Department of Pediatrics, Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York NY, USA
Rupa Mirmira
Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York NY, USA
Ethan Hourizadeh
Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York NY, USA
Dalia Kaufman
The Mindich Child Health and Development Institute, Department of Pediatrics, Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York NY, USA
Bruce D. Gelb
The Mindich Child Health and Development Institute, Department of Pediatrics, Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York NY, USA; Corresponding author
Ross Cagan
Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York NY, USA; Corresponding author
Summary: RASopathies represent a family of mostly autosomal dominant diseases that are caused by missense variants in the rat sarcoma viral oncogene/mitogen activated protein kinase (RAS/MAPK) pathway including KRAS, NRAS, BRAF, RAF1, and SHP2. These variants are associated with overlapping but distinct phenotypes that affect the heart, craniofacial, skeletal, lymphatic, and nervous systems. Here, we report an analysis of 13 Drosophila transgenic lines, each expressing a different human RASopathy isoform. Similar to their human counterparts, each Drosophila line displayed common aspects but also important differences including distinct signaling pathways such as the Hippo and SAPK/JNK signaling networks. We identified multiple classes of clinically relevant drugs—including statins and histone deacetylase inhibitors—that improved viability across most RASopathy lines; in contrast, several canonical RAS pathway inhibitors proved less broadly effective. Overall, our study compares and contrasts a large number of RASopathy-associated variants including their therapeutic responses.
