Abstract IA17: Use of RAS isoforms in nerve tumors

Abstract Neurofibromatosis Type I (NF1) is a common genetic disorder caused by mutations in the NF1 gene, which encodes a RAS-GAP. NF1 loss of function renders patients susceptible to tumors including NF1-/- benign neurofibromas, which can transform into atypical neurofibromas with NF1 and CDKN2A loss, and then lethal malignant peripheral nerve sheath tumors with NF1. CDKN2A, and PRC2 component loss. NF1 mutations are also common in many sporadic cancers. NF1 loss is known to increase or prolong wild type RAS activation, but the relative contribution of RAS paralogs (classical H-, N-, K-RAS and non-classical R-RAS, TC21, MRAS) to NF1 nerve tumorigenesis remains unknown. Our goal was to define the critical RAS paralog mediating the effect of NF1 protein deficiency due to NF1 mutations in neurofibromas and atypical neurofibromas, and to test whether targeting specific RAS paralogs might provide therapeutic strategies. Our data shows that KRAS is activated in RAS protein in NF1-deficient human and mouse Schwann cells (SCs), and in atypical Schwann cells. We find that a PKC agonist, prostratin, known to kill KRAS mutant cells, also selectively kills NF1 mutant Schwann cells in vitro and in mouse neurofibromas, and reduces tumor growth in a xenograft model of atypical neurofibroma. Prostratin acts through use of a subset of PKC isoforms. We anticipate that these findings can ultimately be used to develop an effective RAS targeting therapy for NF1 tumor prevention and treatment. Supported by: NIH R37 NS083580 and R01 NS12082 (N.R.), CancerFree KIDS (N.R.) and a Strauss Fellow Award (L.H.). Citation Format: Nancy Ratner, Liang Hu, Jay Pundavela, Jonathan A. Epstein. Use of RAS isoforms in nerve tumors [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA17.