49 (PB039) - Combined inhibition of SHP2 and CDK4/6 is active in NF1-MPNST

Abstract

Background: 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.