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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Biomarkers, Tumor / genetics*
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Cell Line, Tumor
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Genetic Predisposition to Disease
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Guanosine Triphosphate / metabolism*
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HEK293 Cells
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Humans
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Mice, Inbred BALB C
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Mice, Nude
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mutation*
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Neoplasms / drug therapy
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Neoplasms / enzymology*
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Neoplasms / genetics*
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Neoplasms / pathology
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Neurofibromin 1 / genetics*
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Phenotype
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
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Proto-Oncogene Proteins B-raf / genetics*
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Proto-Oncogene Proteins p21(ras) / genetics*
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SOS1 Protein / metabolism
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Signal Transduction
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
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raf Kinases / metabolism
Substances
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Antineoplastic Agents
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Biomarkers, Tumor
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Enzyme Inhibitors
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KRAS protein, human
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NF1 protein, human
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Neurofibromin 1
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SOS1 Protein
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Guanosine Triphosphate
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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raf Kinases
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinase Kinases
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Proto-Oncogene Proteins p21(ras)