MEK Inhibition Synergizes with TYK2 Inhibitors in NF1-Associated Malignant Peripheral Nerve Sheath Tumors

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Malignant peripheral nerve sheath tumors (MPNST) are aggressive and have poor prognoses.
• Approximately 50% of MPNST cases are linked to neurofibromatosis type 1 (NF1).
• TYK2 (tyrosine kinase 2) is overexpressed in most MPNST, identifying it as a potential therapeutic target.

Purpose of the Study:

• To investigate the therapeutic potential of pharmacologic TYK2 inhibition in MPNST.
• To evaluate the effects of TYK2 inhibition alone and in combination with MEK inhibition on MPNST cell proliferation and survival.

Main Methods:

• In vitro studies utilized IncuCyte live cell assays to assess proliferation and apoptosis.
• RNA-sequencing (RNA-seq), qPCR arrays, and automated Western blotting (WES) were used to analyze downstream effects.
• In vivo efficacy was tested using murine and human MPNST cell lines and patient-derived xenografts (PDX).

Main Results:

• TYK2 inhibition dose-dependently reduced MPNST proliferation and induced apoptosis.
• RNA-seq revealed decreased expression in cell cycle, mitotic, and glycolysis pathways upon TYK2 inhibition.
• A compensatory upregulation of the MEK/ERK pathway was observed, which was effectively targeted by combination therapy.
• Dual TYK2 and MEK inhibition synergistically reduced proliferation and increased apoptosis in vitro and inhibited tumor growth in vivo.

Conclusions:

• Pharmacologic TYK2 inhibition demonstrates significant preclinical efficacy against MPNST.
• Combination therapy with MEK inhibitors shows synergistic effects, offering a promising treatment strategy.
• These findings support the development of a Phase I clinical trial for deucravacitinib and mirdametinib in NF1-associated MPNST.