Econazole selectively induces cell death in NF1-homozygous mutant tumor cells

Cutaneous neurofibromas (cNFs) are tumors that develop in more than 99% of individuals with neurofibromatosis type 1 (NF1). They develop in the dermis and can number in the thousands. cNFs can be itchy and painful and negatively impact self-esteem. There is no US Food and Drug Administration (FDA)-approved drug for their treatment. Here, we screen a library of FDA-approved drugs using a cNF cell model derived from human induced pluripotent stem cells (hiPSCs) generated from an NF1 patient. We engineer an NF1 mutation in the second allele to mimic loss of heterozygosity, differentiate the NF1^+/- and NF1^-/- hiPSCs into Schwann cell precursors (SCPs), and use them to screen a drug library to assess for inhibition of NF1^-/- but not NF1^+/- cell proliferation. We identify econazole nitrate as being effective against NF1^-/- hiPSC-SCPs. Econazole cream selectively induces apoptosis in Nf1^-/- murine nerve root neurosphere cells and human cNF xenografts. This study supports further testing of econazole for cNF treatment.