RT Journal Article
SR Electronic
T1 Efficacy of SHP2 phosphatase inhibition in cancers with nucleotide-cycling oncogenic RAS, RAS-GTP dependent oncogenic BRAF and NF1 loss
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 188730
DO 10.1101/188730
A1 Robert J. Nichols
A1 Franziska Haderk
A1 Carlos Stahlhut
A1 Christopher J. Schulze
A1 Golzar Hemmati
A1 David Wildes
A1 Christos Tzitzilonis
A1 Kasia Mordec
A1 Abby Marquez
A1 Jason Romero
A1 Daphne Hsieh
A1 Gert Kiss
A1 Elena S. Koltun
A1 Adrian L. Gill
A1 Mallika Singh
A1 Mark A. Goldsmith
A1 Jacqueline A. M. Smith
A1 Trever G. Bivona
YR 2017
UL http://biorxiv.org/content/early/2017/09/14/188730.abstract
AB 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 human cancers. While BRAF and MEK inhibitors are effective in many patients with oncogenic BRAF V600E, there are no effective targeted therapies for individuals with cancers driven by other pathway alterations, including oncogenic KRAS, non-V600E BRAF, and NF1 loss. Here, we show that targeting the PTPN11/SHP2 phosphatase with a novel small molecule allosteric inhibitor is effective against cancers bearing nucleotide-cycling oncogenic RAS (e.g. KRAS G12C), RAS-GTP dependent oncogenic BRAF (e.g. class 3 BRAF mutants), or NF1 loss in multiple preclinical models in vitro and in vivo. SHP2 inhibition suppressed the levels of RAS-GTP and phosphorylated ERK in these models and induced growth inhibition. Expression of a constitutively active mutant of the RAS guanine nucleotide exchange factor (GEF) SOS1 rescued cells from the effects of SHP2 inhibition, suggesting that SHP2 blockade decreases oncogenic RAS-RAF-MEK-ERK signaling 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 thus represents a rational, biomarker-driven therapeutic strategy to be tested in patients with cancers of diverse origins bearing these oncogenic drivers and for which current treatments are largely ineffective.