Melanoma is the third most diagnosed cancer with 16,878 new cases in Australia in 2021 (Australian Institute of Health and Welfare). Current treatment strategies involve surgery, immunotherapy and therapy targeting the BRAF/MEK/ERK pathway. Obese and overweight melanoma patients treated with either immune or targeted therapy show increased overall survival [1], which is contraindicative as obesity increases the risk of cancer. In this study the underlying mechanism of how adiposity enhances targeted therapy efficacy is investigated. Inhibition of the BRAF/MEK/ERK pathway initially decreases tumour growth, often followed by a drug tolerant cell state leading to minimal residual disease (MRD) and then resistance develops resulting in tumour growth. MRD is due to non-mutational mediated transcriptional changes and several distinct transcriptional cell states have been identified. Recently up to four transcriptional cell states were described: SMC (starved-like melanoma cell), NCSC (neural crest stem cell), pigmented and invasive [2]. As a first step in this study we are examining if these transcriptional cell states can be recapitulated in vitro. In addition, we are assessing the role of Retinoid X Receptors (RXR) and Liver X Receptors (LXR). RXR is upregulated in the NCSC state, the cell state that is thought to be a major contributor to the development of resistance [2]. In addition, RXR heterodimerizes with LXR, which is likely activated in obese patients by increased circulating oxysterols. LXR activation decreases signalling pathways involved in BRAF/MEK inhibitor resistance, suggesting this receptor could be a key driver in improving the treatment efficacy in obese patients [3,4].