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

Abstract

<div>AbstractPurpose:<p>Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited treatment options and poor survival rates. About half of MPNST cases are associated with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Overexpression of TYK2 occurs in the majority of MPNST, implicating TYK2 as a therapeutic target.</p>Experimental Design:<p>The effects of pharmacologic TYK2 inhibition on MPNST cell proliferation and survival were examined using IncuCyte live cell assays <i>in vitro</i>, and downstream actions were analyzed using RNA-sequencing (RNA-seq), qPCR arrays, and validation of protein changes with the WES automated Western system. Inhibition of TYK2 alone and in combination with MEK inhibition was evaluated <i>in vivo</i> using both murine and human MPNST cell lines, as well as MPNST PDX.</p>Results:<p>Pharmacologic inhibition of TYK2 dose-dependently decreased proliferation and induced apoptosis over time. RNA-seq pathway analysis on TYK2 inhibitor–treated MPNST demonstrated decreased expression of cell cycle, mitotic, and glycolysis pathways. TYK2 inhibition resulted in upregulation of the MEK/ERK pathway gene expression, by both RNA-seq and qPCR array, as well as increased pERK1/2 levels by the WES Western system. The compensatory response was tested with dual treatment with TYK2 and MEK inhibitors, which synergistically decreased proliferation and increased apoptosis <i>in vitro</i>. Finally, combination therapy was shown to inhibit growth of MPNST in multiple <i>in vivo</i> models.</p>Conclusions:<p>These data provide the preclinical rationale for the development of a phase I clinical trial of deucravacitinib and mirdametinib in NF1-assosciated MPNST.</p></div>

PROTACs: A novel strategy for cancer drug discovery and development

“…MEK1 and MEK2 (mitogen activated protein kinase) are two family members of MAP kinase, which are important signaling molecules in the Ras–RAF–MEK–ERK pathway. 288 MEK1 and MEK2 activate downstream ERK to promote growth and survival of cancer cells, thus playing an important role in tumor development. 289 , 290 …”