Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition

Jonathan R. LaRochelle, Michelle Fodor, Vidyasiri Vemulapalli, Morvarid Mohseni, Ping Wang, Travis Stams, Matthew J. LaMarche, Rajiv Chopra, Michael G. Acker () and Stephen C. Blacklow ()
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Jonathan R. LaRochelle: Harvard Medical School
Michelle Fodor: Novartis Institutes for Biomedical Research
Vidyasiri Vemulapalli: Harvard Medical School
Morvarid Mohseni: Novartis Institutes for Biomedical Research
Ping Wang: Novartis Institutes for Biomedical Research
Travis Stams: Novartis Institutes for Biomedical Research
Matthew J. LaMarche: Novartis Institutes for Biomedical Research
Rajiv Chopra: Novartis Institutes for Biomedical Research
Michael G. Acker: Novartis Institutes for Biomedical Research
Stephen C. Blacklow: Harvard Medical School

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract Activating mutations in PTPN11, encoding the cytosolic protein tyrosine phosphatase SHP2, result in developmental disorders and act as oncogenic drivers in patients with hematologic cancers. The allosteric inhibitor SHP099 stabilizes the wild-type SHP2 enzyme in an autoinhibited conformation that is itself destabilized by oncogenic mutations. Here, we report the impact of the highly activated and most frequently observed mutation, E76K, on the structure of SHP2, and investigate the effect of E76K and other oncogenic mutations on allosteric inhibition by SHP099. SHP2E76K adopts an open conformation but can be restored to the closed, autoinhibited conformation, near-identical to the unoccupied wild-type enzyme, when complexed with SHP099. SHP099 inhibitory activity against oncogenic SHP2 variants in vitro and in cells scales inversely with the activating strength of the mutation, indicating that either oncoselective or vastly more potent inhibitors will be necessary to suppress oncogenic signaling by the most strongly activating SHP2 mutations in cancer.

Date: 2018
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DOI: 10.1038/s41467-018-06823-9

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