Abstract IA010: Novel targeted therapy approaches in NF1-MPNST

Abstract

Abstract NF1 is an essential negative regulator of RAS activity and its function is lost in nearly 90% of malignant peripheral nerve sheath tumors (MPNST). Additional recurrent molecular changes include loss of function alterations in CDKN2A, TP53, EED and SUZ12, but molecular targeting of these genomic events represents a unique challenge. We previously reported that the efficacy of MEK inhibitor is limited by adaptive activation of receptor tyrosine kinases and the adaptor protein SHP2, and that combined inhibition of MEK and SHP2 is effective in MPNST. However, the clinical potential of combination MEK and SHP2 inhibitors may be limited by the overlapping toxicity induced by ERK pathway inhibition. Genetic depletion of PTPN11 has substantial growth inhibitory effects in preclinical models of MPNST, suggesting that SHP2 is an exciting new focus for targeted therapy development in NF1-MPSNT. Loss of CDKN2A, inactivation of RB1, and hyperactivation of cyclin dependent kinases (CDK) in MPNST also suggest that small-molecule CDK4/6 inhibitors (CDK4/6i) may offer a potential combination strategy. Our preclinical data suggest that this combination is active, well-tolerated, and has the potential for immediate advancement into clinical trials. Citation Format: Christine A. Pratilas. Novel targeted therapy approaches in NF1-MPNST [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr IA010.