Novel RXR agonist for neurofibromatosis

This preclinical study evaluates the novel retinoid X receptor (RXR) agonist MSU-42011 as a therapeutic strategy for tumors associated with neurofibromatosis type 1 (NF1). NF1 is an inherited disorder in which roughly half of affected individuals develop plexiform neurofibromas (PNFs) that can progress to malignant peripheral nerve sheath tumors (MPNSTs). Existing treatment with the MEK inhibitor selumetinib has clinical benefit for PNFs but is limited by reduced efficacy against MPNSTs and dose-limiting toxicities. Motivated by the role of NF1 deficiency in driving tumorigenesis via RAS hyperactivation and the prominent macrophage infiltration in NF1 lesions, the team explored whether targeting tumor-promoting immune cells with an RXR agonist could provide an alternative or complementary therapeutic approach.

Using both in vitro and in vivo models, the investigators compared the effects of MSU-42011, selumetinib, and their combination on NF1-deficient cells and a syngeneic MPNST mouse model. In cellular assays, both MSU-42011 and selumetinib reduced levels of phosphorylated ERK (pERK), an indicator of MAPK pathway activation, with the combination producing greater reductions than either agent alone. Conditioned media from NF1-deficient cells induced increased expression of multiple cytokines and chemokines in human THP1 monocytes and in bone marrow–derived macrophages (BMDMs), reflecting a tumor-driven inflammatory signaling milieu. Treatment with MSU-42011 or selumetinib, alone or in combination, partially reversed these inductions, suggesting the agents can modulate tumor–immune signaling that may support tumor progression.

In syngeneic MPNST models, combination therapy produced pronounced antitumor effects: tumor growth was significantly reduced relative to controls, intratumoral pERK levels decreased, tumor-promoting macrophage markers declined, and activated CD8+ T cell infiltration increased. The study also reports dose ranges and comparative agents in related experiments—MSU-42011 tested at multiple doses (12.5–100 mg/kg) and comparison with bexarotene in a lung cancer model—illustrating that MSU-42011 has demonstrable pharmacologic activity in vivo. Across models, the combination of RXR agonism with MEK inhibition achieved greater suppression of tumor-promoting signaling and immune phenotypes than either approach alone.

These findings support the hypothesis that RXR agonists can reshape the tumor immune microenvironment in NF1-associated tumors while also impacting oncogenic signaling downstream of RAS. The observed reduction in tumor-promoting macrophages together with increased CD8+ T cell activation highlights a dual mechanism—direct modulation of tumor signaling and reprogramming of pro-tumor immune components—that may underlie the therapeutic activity of MSU-42011. The authors conclude that RXR agonists merit further investigation in NF1, and that combining RXR agonists with MEK inhibitors like selumetinib could represent a promising strategy to improve outcomes for patients with PNFs and MPNSTs.