Background:

Neurofibromatosis type 1 (NF1) is a tumor-predisposing condition caused by mutations in the NF1 gene which encodes neurofibromin, a Ras-GTPase activating protein. Loss of both copies of NF1 in Schwann cells (SCs) results misregulation of Ras signaling and the formation of benign tumors, the most common being plexiform neurofibromas (PNs). Currently, the MEK inhibitor Selumetinib is the only FDA-approved treatment for NF1-associated tumors.

Methods:

To discover new therapeutic targets, we used pairs of NF1-deficient (NF1^-/-) and normal (NF1^-/+) SCs, either from patients or engineered by CRISPR-gene editing for profiling the activated kinome, total proteome and phosphoproteome, and transcriptomic signatures. By identifying the molecular fingerprint associated with NF1 loss and subsequent interrogation and perturbation of signaling networks altered between NF1^-/- and NF1^-/+ SCs, we hope to reveal novel therapeutic targets for treating NF1-deficient tumors.

Results:

Comparative analyses between isogenic sets of patient-derived SCs identified several signaling pathways with altered activity upon NF1 loss, which we confirmed using RT-qPCR and western blotting. Based on these findings, we tested single-agent therapeutics targeting these pathways that demonstrate preferential sensitivity to NF1^-/- SCs compared to NF1^-/+ SCs.

Conclusions:

The therapeutics identified could result in novel treatment options for NF1-associated tumors. Biomarkers discovered may facilitate the assessment of treatments.