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The RXR Agonist MSU42011 Is Effective for the Treatment of Preclinical HER2+ Breast Cancer and Kras-Driven Lung
Ana S Leal1, Jessica A Moerland1, Di Zhang1
1Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA.
Abstract:
(1) Background: Notwithstanding numerous therapeutic advances, 176,000 deaths from breast and lung cancers will occur in the United States in 2021 alone. The tumor microenvironment and its modulation by drugs have gained increasing attention and relevance, especially with the introduction of immunotherapy as a standard of care in clinical practice. Retinoid X receptors (RXRs) are members of the nuclear receptor superfamily and upon ligand binding, function as transcription factors to modulate multiple cell functions. Bexarotene, the only FDA-approved RXR agonist, is still used to treat cutaneous T-cell lymphoma. (2) Methods: To test the immunomodulatory and anti-tumor effects of MSU42011, a new RXR agonist, we used two different immunocompetent murine models (MMTV-Neu mice, a HER2 positive model of breast cancer and the A/J mouse model, in which vinyl carbamate is used to initiate lung tumorigenesis) and an immunodeficient xenograft lung cancer model. (3) Results: Treatment of established tumors in immunocompetent models of HER2-positive breast cancer and Kras-driven lung cancer with MSU42011 significantly decreased the tumor burden and increased the ratio of CD8/CD4, CD25 T cells, which correlates with enhanced anti-tumor efficacy. Moreover, the combination of MSU42011 and immunotherapy (anti-PDL1 and anti-PD1 antibodies) significantly (p < 0.05) reduced tumor size vs. individual treatments. However, MSU42011 was ineffective in an athymic human A549 lung cancer xenograft model, supporting an immunomodulatory mechanism of action. (4) Conclusions: Collectively, these data suggest that the RXR agonist MSU42011 can be used to modulate the tumor microenvironment in breast and lung cancer.
Insights
A new Retinoid X receptor (RXR) agonist, MSU42011, shows promise in reducing breast and lung tumor burden by modulating the tumor microenvironment. Its combination with immunotherapy significantly enhances anti-tumor efficacy in preclinical models.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Despite advances, breast and lung cancers cause significant mortality.
- The tumor microenvironment's role in cancer progression and treatment is increasingly recognized.
- Retinoid X receptors (RXRs) are nuclear receptors that regulate cellular functions; bexarotene is an FDA-approved RXR agonist.
Purpose of the Study:
- To evaluate the immunomodulatory and anti-tumor effects of a novel RXR agonist, MSU42011.
- To assess MSU42011's efficacy in preclinical models of breast and lung cancer.
- To investigate MSU42011's potential in combination with immunotherapy.
Main Methods:
- Tested MSU42011 in immunocompetent murine models (HER2+ breast cancer, Kras-driven lung cancer) and an immunodeficient lung cancer xenograft model.
- Assessed tumor burden, immune cell infiltration (CD8/CD4, CD25 T cells), and response to combination therapy with anti-PDL1/anti-PD1 antibodies.
- Utilized MMTV-Neu and A/J mouse models, and a human A549 xenograft model.
Main Results:
- MSU42011 significantly reduced tumor burden in immunocompetent models.
- Treatment increased CD8/CD4 and CD25 T cell ratios, indicating enhanced anti-tumor immunity.
- Combination therapy with MSU42011 and immunotherapy markedly reduced tumor size compared to monotherapy.
- MSU42011 showed no efficacy in an immunodeficient xenograft model, supporting an immunomodulatory mechanism.
Conclusions:
- The RXR agonist MSU42011 demonstrates significant anti-tumor activity in breast and lung cancer models.
- MSU42011 effectively modulates the tumor microenvironment, enhancing immune responses.
- MSU42011 holds potential as a therapeutic agent, particularly in combination with cancer immunotherapies.
