# The RXR Agonist MSU-42011 Reduces Tumor Burden in a Murine Preclinical NF1-Deficient Model

## TL;DR

A new drug called MSU-42011, when combined with an existing treatment, shows promise in reducing tumor growth in a mouse model of a genetic disorder called NF1.

## Contribution

MSU-42011, an RXR agonist, is shown to reduce tumor burden in NF1-deficient models, both alone and in combination with selumetinib.

## Key findings

- MSU-42011 reduced tumor growth, pERK levels, and tumor-promoting immune cells in NF1-deficient models.
- Combining MSU-42011 with selumetinib further reduced tumor growth and suppressed pro-tumor cytokine signaling.
- The combination therapy increased activated CD8+ T cells and reduced tumor-promoting macrophages in MPNST models.

## Abstract

Neurofibromatosis type 1 (NF1) is a genetic disorder that leads to the formation of plexiform neurofibromas (PNFs), which can progress to malignant peripheral nerve sheath tumors (MPNSTs), a major cause of death in individuals with NF1. Current treatments, like the MEK inhibitor selumetinib, are limited to PNFs and have significant side effects, highlighting the urgent need for more effective therapies. Our research identified MSU-42011, a retinoid X receptor (RXR) agonist, as a promising candidate in preclinical NF1-deficient models. MSU-42011 reduced tumor growth, pERK levels, and tumor-promoting immune cells, while increasing activated T cells; further tumor reduction was observed when combined with selumetinib. The combination therapy also suppressed pro-tumor cytokine signaling, suggesting potential for immune modulation. These findings highlight RXR agonists as an effective therapeutic strategy for NF1, with combination therapy offering a promising treatment option.

Background/Objectives: Neurofibromatosis type 1 (NF1) is a prevalent inherited disorder, with approximately 50% of affected individuals developing plexiform neurofibromas (PNFs), which can progress to highly aggressive malignant peripheral nerve sheath tumors (MPNSTs). While selumetinib is FDA-approved for PNFs, its efficacy in MPNSTs is limited and associated with dose-limiting toxicities. NF1 deficiency drives tumorigenesis and alters immune dynamics via RAS hyperactivation. Given the substantial macrophage infiltration in NF1 lesions and its association with disease progression, we hypothesized that targeting tumor-promoting immune cells with the retinoid X receptor (RXR) agonist MSU-42011 could be an alternative therapeutic strategy, as it has shown promise in KRAS-driven cancers by decreasing pERK levels and reducing tumor-promoting immune cells. Methods: We examined the effects of MSU-42011 and selumetinib, alone and in combination, on NF1-deficient cells and in a syngeneic MPNST model. Results: In vivo, the combination of MSU-42011 and selumetinib significantly reduced tumor growth, pERK levels, and tumor-promoting macrophages and increased activated CD8+ T cells in syngeneic MPNST models. In NF1-deficient cells, MSU-42011 or selumetinib reduced pERK levels, with combination treatment achieving greater reductions. Conditioned media (CM) from NF1-deficient cells increased the protein and mRNA levels of several cytokines and chemokines in human THP1 cells and bone marrow-derived macrophages (BMDMs). MSU-42011 and selumetinib, alone or in combination, partially reversed this induction. Conclusions: These findings suggest RXR agonists may have therapeutic potential against NF1, and their combination with MEK inhibitors could represent a promising strategy for NF1-associated tumors. Further studies are needed to validate these results and assess their translational relevance.