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

Jiawan Wang, Kai Pollard, Amy N. Allen, Tushar Tomar, Dirk Pijnenburg, Zhan Yao, Fausto J. Rodriguez, Christine A. Pratilas

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)5367-5379
Number of pages13
JournalCancer Research
Volume80
Issue number23
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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