Hyperactive Ras as a therapeutic target in neurofibromatosis type 1

The NF1 gene encodes neurofibromin, a GTPase-activating protein (GAP) for m embers of the p21(ras) (Ras) family, which negatively regulates Ras output by accelerating the conversion of active Ras GTP to inactive Ras-GDP. Analy sis of tumors from patients with neurofibromatosis type 1 (NF1) has shown b iochemical evidence of hyperactive Ras as well as frequent loss of the norm al NF1 allele, consistent with its role as a tumor suppressor gene. Taken t ogether, these data suggest that novel therapeutics directed against compon ents of the Ras signaling cascade might provide effective treatments for ce rtain pathological complications of NF1. Here we summarize data that suppor t a role for hyperactive Ras in NF1 disease, including Ras processing, acti vation,and down-regulation. We review targets for rational drug design, pro vide preliminary results, and discuss implications for future studies. Am. J. Med. Genet. (Semin. Med. Genet.) 89:14-22, 1999. (C) 1999 Wiley-Liss, In c.