# Understanding and targeting MAPK pathway activation in NF1-deficient malignant peripheral nerve sheath tumor (MPNST)

> **NIH NIH U01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $616,953

## Abstract

Project Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) represent a group of highly aggressive soft tissue
sarcomas that occur in distinct clinical settings: neurofibromatosis 1 (NF1)-associated (45%), sporadic (45%) or
radiotherapy (RT)-associated (10%). MPNSTs metastasize early and are resistant to radiotherapy and systemic
chemotherapy and have poor prognosis. Irrespective of the clinical settings, MPNSTs share the same molecular
pathway inactivation in NF1 (>90%, hence NF1-deficient), Polycomb repressive complex 2 (PRC2), and
CDKN2A through biallelic genetic alterations, suggesting that they can be molecularly targeted similarly. NF1-
deficient plexiform neurofibroma responds well to MEK inhibitor (MEKi) treatment clinically; however, NF1-
deficeint MPNSTs arising from plexiform neurofibromas are universally resistant to MEKi, suggesting intrinsic
resistance in the more aggressive form of peripheral nerve sheath tumors. Using MPNST patient tumor samples
and preclinical MPNST models, we have uncovered that PRC2-loss leads to PDGRA upregulation; MEKi
treatment resulted in feedback upregulation of PDGFRB irrespective of the PRC2 status. The convergence of
the PDGFR pathway activation by different mechanisms points to a novel therapeutic opportunity to target the
PDGFR pathway to overcome MEKi resistance in MPNST. Combination of a novel PDGFRA/B inhibitor, ripretinib
with a MEKi leads to synergistic growth inhibition of MPNST in vitro and in vivo. We hypothesize that
PDGFRA/B pathway activation represent a central resistance mechanism to MEKi and combined
targeting of the PDGFR and MAPK pathways with ripretinib (pan-PDGFRA/B inhibitor) and binimetinib
(MEKi) may present an effective therapeutic strategy in NF1-deficient MPNST.
Here, we propose to investigate the tumor heterogeneity and cellular plasticity involved in tumor evolution and
adaptive resistance to binimetinib and combination of ripretinib and binimetinib, using well-defined preclinical
MPNST in vitro and in vivo model systems and single-cell analysis including single cell RNA-seq (scRNA-seq)
and a novel barcoding system. Additionally, we propose a collaborative clinical investigation between CCR/NCI
(Drs. Widemann/Shern) and MSKCC (Dr. Chi) to conduct a proof-of-concept phase I/II study of the combination
of ripretinib and binimetinib in patients with NF1-deficient MPNST. In this trial, we will assess and optimize the
evaluation of MAPK pathway inhibition to the ripretinib/binimetinib combination therapy using traditional ERK
phosphorylation and newly established custom Pea3-family ETS-regulated MAPK signature. Further, we will
also investigate the tumor heterogeneity and cellular plasticity in tumor evolution and resistance mechanisms to
the ripretinib/binimetinib combination using targeted NGS, scRNA-seq and integrative analysis. The proposal
leverages the synergistic expertise and resources at MSKCC and CCR/NCI. We believe that these studies will
generate mechanistic ins...

## Key facts

- **NIH application ID:** 10376770
- **Project number:** 5U01CA252048-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Ping Chi
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $616,953
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376770

## Citation

> US National Institutes of Health, RePORTER application 10376770, Understanding and targeting MAPK pathway activation in NF1-deficient malignant peripheral nerve sheath tumor (MPNST) (5U01CA252048-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10376770. Licensed CC0.

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