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
  • 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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