RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers
2018; Nature Portfolio; Volume: 20; Issue: 9 Linguagem: Inglês
10.1038/s41556-018-0169-1
ISSN1476-4679
AutoresRobert J. Nichols, Franziska Haderk, Carlos Stahlhut, Christopher J. Schulze, Golzar Hemmati, David Wildes, Christos Tzitzilonis, Kasia Mordec, Abby Marquez, Jason M. Romero, Tientien Hsieh, Aubhishek Zaman, Victor Olivas, Caroline E. McCoach, Collin M. Blakely, Zhengping Wang, Gert Kiss, Elena S. Koltun, Adrian L. Gill, Mallika Singh, Mark A. Goldsmith, Jacqueline A.M. Smith, Trever G. Bivona,
Tópico(s)Protein Kinase Regulation and GTPase Signaling
ResumoOncogenic alterations in the RAS/RAF/MEK/ERK pathway 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 non-V600E oncogenic BRAF, RAS GTPase-activating protein (GAP) NF1 (neurofibromin 1) loss and oncogenic KRAS. Here, we show that targeting the SHP2 phosphatase (encoded by PTPN11) with RMC-4550, a small-molecule allosteric inhibitor, is effective in human cancer models bearing RAS-GTP-dependent oncogenic BRAF (for example, class 3 BRAF mutants), NF1 loss or nucleotide-cycling oncogenic RAS (for example, KRASG12C). SHP2 inhibitor treatment decreases oncogenic RAS/RAF/MEK/ERK signalling and cancer growth by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS/MAPK pathway activation in cancers with RAS-GTP-dependent oncogenic BRAF, NF1 loss and nucleotide-cycling oncogenic KRAS. SHP2 inhibition is a promising molecular therapeutic strategy for patients with cancers bearing these oncogenic drivers.
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