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

Abstract

Purpose: 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. Experimental Design: The effects of pharmacologic TYK2 inhibition on MPNST cell proliferation and survival were examined using IncuCyte live cell assays in vitro, and downstream actions were analyzed using RNAseq, 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 in vivo using both murine and human MPNST cell lines, as well as MPNST PDX. Results: Pharmacologic inhibition of TYK2 dose-dependently decreased proliferation and induced apoptosis over time. RNAseq 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 WES Western system. The compensatory response was tested with dual treatment with TYK2 and MEK inhibitors, which synergistically decreased proliferation and increased apoptosis in vitro. Finally, combination therapy was shown to inhibit growth of MPNST in multiple in vivo models. Conclusions: These data provide the preclinical rationale for the development of a phase 1 clinical trial of deucravacitinib and mirdametinib in NF1-assosciated MPNST.

Analysis of treatment sequence and outcomes in patients with relapsed malignant peripheral nerve sheath tumors

“… 46 Additionally, signal transducer and activator of transcription-3 (STAT3) has also been implicated in MPNST oncogenesis and so, tyrosine kinase 2 (TYK2), involved in STAT protein activation, inhibitors in combination with mitogen-activated protein kinase kinase (MEK) inhibitors have shown potential in models of NF1-associated MPNST. 47 Recently, the src homology region 2 (SH2)-containing protein tyrosine phosphatase-2 (SHP2) has gained attention in its role in adaptive signaling driven by receptor tyrosine kinase activation and preclinical data in MPNST demonstrate therapeutic efficacy of combined inhibition of SHP2 and MEK 48 or cyclin-dependent kinase 4/6 (CDK4/6). 49 Additionally, there is a growing interesting in immunotherapeutic approaches in the treatment of MPNST, alone or in combination with molecularly targeted therapies, although no clinical trials have demonstrated overall benefits of immune checkpoint blockade (ICB) to date in MPNST.…”

Potential applications of JAK inhibitors, clinically approved drugs against autoimmune diseases, in cancer therapy

“…Deucravacitinib (Sotyktu™), a specific inhibitor against TYK2, was approved for treatment of moderate-to-severe plaque psoriasis (PP) in 2022 by the FDA ( Papp et al, 2018 ). Overexpression of TYK2 occurs in the majority of malignant peripheral nerve sheath tumors (MPNST); inhibition of TYK2 by deucravacitinib decreased proliferation and induced apoptosis of these tumors through decreased expression of proteins involved in the cell cycle, mitotic, and glycolysis pathways ( Borcherding et al, 2023 ). It has been reported that therapeutic TYK2 inhibition may increase the risk of lung cancer and NHL; however, the safety profile of deucravacitinib has not yet been determined ( Yarmolinsky et al, 2022 ).…”

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 The Jin group has been engaged in the discovery of a variety of MEK degraders based on VHL and CRBN E3 ligands.…”