LAUSR

Oncogenic alterations in the RAS-RAF-MEK-ERK pathway, including mutant forms of KRAS, BRAF, and loss of the tumor suppressor and RAS GTPase-activating protein (GAP) NF1, drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAFV600E-driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including oncogenic KRAS, NF1 loss, and non-V600E oncogenic BRAF. Here, we show that targeting the PTPN11/SHP2 phosphatase with a novel small molecule allosteric inhibitor is effective in human cancer models bearing nucleotide-cycling oncogenic RAS (e.g. KRASG12C), NF1 loss, or RAS-GTP dependent oncogenic BRAF (e.g. class 3 BRAF mutants). SHP2 inhibitor treatment decreases oncogenic RAS-RAF-MEK-ERK signaling and cancer growth by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS activation and downstream signaling in cancers with nucleotide-cycling oncogenic RAS, RAS-GTP dependent oncogenic BRAF, and NF1 loss. SHP2 inhibition is a promising molecular therapeutic strategy for patients with cancers bearing these oncogenic drivers. Citation Format: Trever G. Bivona, Robert Nichols, Franziska Haderk, Carlos Stahlhut,Christopher Schulze, Golzar Hemmati, David Wildes. Efficacy of SHP2 phosphatase inhibition in cancers with nucleotide-cycling oncogenic RAS, NF1 loss and RAS-GTP-dependent oncogenic BRAF [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3993.