Format

Send to

Choose Destination
Nat Cell Biol. 2018 Sep;20(9):1064-1073. doi: 10.1038/s41556-018-0169-1. Epub 2018 Aug 13.

RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers.

Author information

1
Department of Biology, Revolution Medicines, Inc., Redwood City, CA, USA.
2
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
3
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
4
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
5
Department of Development Sciences, Revolution Medicines, Inc., Redwood City, CA, USA.
6
Department of Chemistry, Revolution Medicines, Inc., Redwood City, CA, USA.
7
Department of Biology, Revolution Medicines, Inc., Redwood City, CA, USA. jan@revolutionmedicines.com.
8
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. trever.bivona@ucsf.edu.
9
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. trever.bivona@ucsf.edu.
10
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. trever.bivona@ucsf.edu.

Abstract

Oncogenic 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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center