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

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

  • Nat Cell Biol. 2018 Sep;20(9):1064-1073. doi: 10.1038/s41556-018-0169-1.
Robert J Nichols 1,  Franziska Haderk 2 3 4,  Carlos Stahlhut 1,  Christopher J Schulze 1,  Golzar Hemmati 2 3 4,  David Wildes 1,  Christos Tzitzilonis 1,  Kasia Mordec 1,  Abby Marquez 1,  Jason Romero 1,  Tientien Hsieh 1,  Aubhishek Zaman 2 3 4,  Victor Olivas 2 3 4,  Caroline McCoach 2,  Collin M Blakely 2,  Zhengping Wang 5,  Gert Kiss 1,  Elena S Koltun 6,  Adrian L Gill 6,  Mallika Singh 1,  Mark A Goldsmith 1 6,  Jacqueline A M Smith 7,  Trever G Bivona 8 9 10
Affiliations

Affiliations

  • 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. [email protected].
  • 8 Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. [email protected].
  • 9 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. [email protected].
  • 10 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. [email protected].
PMID: 30104724 DOI: 10.1038/s41556-018-0169-1
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.

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