Abstract 2986: NR2F1 underlies persistence of residual disease in melanoma

Abstract

Abstract Despite the clinical success of targeted therapy and checkpoint inhibitors in melanoma, therapeutic responses are transient, followed by relapse that may be driven by a small subpopulation of residual or drug-tolerant cells. Understanding residual disease and metastasis mechanisms can provide clues both for developing improved versions of a drug and for guiding the selection of appropriate drug combinations for melanoma therapy. Here, we found that the well-known marker of tumor dormancy, Nuclear Receptor Subfamily 2 Group F Member 1 (NR2F1), was overexpressed in minimal disease residual cells following CDK4/6 and MEK inhibitors (CDK4/6i+MEKi) treatment in vivo. Furthermore, melanoma cells overexpressing NR2F1 were less sensitive to (CDK4/6i+MEKi) or BRAF and MEK inhibitors (BRAFi+MEKi) treatment in vitro and in vivo models, inhibiting apoptosis. Surprisingly, we did not find any evidence of decreased cell growth in our model. Using a three-dimensional tumor spheroid assay in vitro, we found the NR2F1 expression enhanced melanoma invasion following CDK4/6i+MEKi or BRAFi+MEKi treatments. The use of published RNA Seq data sets that were gathered from the GEO database and Single Cell Seq data sets from PDX melanoma samples showed that high expression of NR2F1 is enriched in the undifferentiated cell state and invasive cells, respectively. Furthermore, BRAF mutant patient sample with an acquired mutation in NRAS Q61R following BRAFi+MEKi+CDKi presented a high expression of NR2F1. Altogether, these findings suggest that NR2F1 may play a role in residual disease persistence besides known features of tumor dormancy, especially important in determining responses to dramatic changes in the environment, such as changes induced by anti-cancer therapy. Citation Format: Manoela Tiago, Jessica L. Teh, Timothy J. Purwin, Weijia Cai, Connor Hollingworth, Melisa Lopez-Anton, Julio A. Aguirre-Ghiso, Andrew E. Aplin. NR2F1 underlies persistence of residual disease in melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2986.