Nuclear hormone receptor targeting suppresses melanoma progression in diverse preclinical models.
Major finding: Nuclear hormone receptor targeting suppresses melanoma progression in diverse preclinical models.
Mechanism: Induction of ApoE by LXRβ leads to suppression of tumor growth, invasion, angiogenesis, and metastasis.
Impact: LXR agonists are potential therapies for primary, metastatic, and therapy-resistant melanoma.
Melanoma is the most aggressive skin cancer due to a propensity to metastasize and resistance to standard therapies. Nuclear hormone receptors are therapeutic targets in reproductive tissues, but their clinical utility in other solid tumors such as melanoma remains undefined. Pencheva and colleagues observed that liver-X nuclear hormone receptor β (LXRβ) was ubiquitously expressed across patient-derived melanoma cell lines and that LXR agonists inhibited invasion and endothelial cell recruitment of multiple melanoma cell lines in vitro in an LXRβ-dependent manner. Furthermore, oral administration of LXR agonists suppressed melanoma xenograft tumor growth, accompanied by a reduction in the number and size of tumoral endothelial vessels as well as lung and brain metastases. LXRβ is a known transcriptional activator of the metastasis suppressor apolipoprotein-E (ApoE), and extracellular ApoE was shown to be the primary mediator of tumor suppression by activated LXR, as antibody-mediated neutralization of ApoE in vitro or systemic ApoE genetic disruption in vivo abrogated LXR agonist antitumor activity. Stroma-specific inactivation of LXRβ, but not tumor-specific LXRβ depletion, rendered LXR agonism ineffective against primary tumor growth, denoting a key role for stromal activation of LXRβ. However, LXRβ-mediated inhibition of metastasis required ApoE induction in both the tumor and stromal compartments. In multiple genetically engineered mouse melanoma models, LXR agonism suppressed primary and metastatic tumor growth and reduced mortality. Moreover, melanoma cells resistant to dacarbazine or the BRAF inhibitor vemurafenib were sensitive to LXRβ agonism, and the combination of LXR agonists with dacarbazine, vemurafenib, or anti-CTLA4–based immunotherapy was cooperative in suppressing the growth of several melanoma cell lines in vivo. These preclinical results provide evidence that LXRβ agonism is a promising therapy for the suppression of genetically diverse melanoma subtypes through transcriptional activation of tumoral and stromal ApoE.