Combined inhibition of SHP2 and MEK is effective in models of NF1-deficient malignant peripheral nerve sheath tumors Journal Article


Authors: Wang, J.; Pollard, K.; Allen, A. N.; Tomar, T.; Pijnenburg, D.; Yao, Z.; Rodriguez, F. J.; Pratilas, C. A.
Article Title: Combined inhibition of SHP2 and MEK is effective in models of NF1-deficient malignant peripheral nerve sheath tumors
Abstract: Loss of the RAS GTPase-activating protein (RAS-GAP) NF1 drives aberrant activation of RAS/MEK/ERK signaling and other effector pathways in the majority of malignant peripheral nerve sheath tumors (MPNST). These dysregulated pathways represent potential targets for therapeutic intervention. However, studies of novel single agents including MEK inhibitors (MEKi) have demonstrated limited efficacy both preclinically and clinically, with little advancement in overall patient survival. By interrogation of kinome activity through an unbiased screen and targeted evaluation of the signaling response to MEK inhibition, we have identified global activation of upstream receptor tyrosine kinases (RTK) that converges on activation of RAS as a mechanism to limit sensitivity to MEK inhibition. As no direct inhibitors of pan-RAS were available, an inhibitor of the protein tyrosine phosphatase SHP2, a critical mediator of RAS signal transduction downstream of multiple RTK, represented an alternate strategy. The combination of MEKi plus SHP099 was superior to MEKi alone in models of NF1-MPNST, including those with acquired resistance to MEKi. Our findings have immediate translational implications and may inform future clinical trials for patients with MPNST harboring alterations in NF1. Significance: Combined inhibition of MEK and SHP2 is effective in models of NF1-MPNST, both those na€ive to and those resistant to MEKi, as well as in the MPNST precursor lesion plexiform neurofibroma. © 2020 American Association for Cancer Research.
Journal Title: Cancer Research
Volume: 80
Issue: 23
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2020-12-01
Start Page: 5367
End Page: 5379
Language: English
DOI: 10.1158/0008-5472.Can-20-1365
PROVIDER: scopus
PMCID: PMC7739379
PUBMED: 33032988
DOI/URL:
Notes: Article -- Export Date: 1 March 2021 -- Source: Scopus
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MSK Authors
  1. Zhan Yao
    37 Yao