Abstract Malignant melanoma is an example of primary clinical significance for investigating sex-related differences in cancer arising in organs with non-reproductive functions. Differences in sex hormone levels and in downstream pathways are likely to play a key role, which is however still poorly understood. Our main working hypothesis is that androgen receptor (AR) and associated proteins converge on control of melanoma development and response to treatment. In recent work, we have found that genetic and pharmacological suppression of AR activity in a large panel of melanoma cells reduces self-renewal potential and tumorigenesis, inducing double strand DNA damage and cytoplasmic leakage, a STING-dependent pro-inflammatory cascade and a gene expression signature associated with better patients' survival. Based on further preliminary data, we will test two specific hypotheses: 1) AR signaling plays a key role in melanoma cells at the intersection between gene transcription and DNA repair / genomic stability with nuclear lamins as co-determinants. We will probe into the biochemical and functional significance of endogenous AR-lamin interactions and AR-dependent lamin A/C association with the PPP1 protein phosphatase, impinging on lamin phosphorylation at critical residues, and with the DDX3X and DDX3Y RNA helicases, encoded by X- and Y-linked genes and with expression of prognostic significance for female and male patients, respectively. 2) Targeting AR is of translational significance for preventing / counteracting resistance of melanomas with BRAFv600 mutations to BRAF inhibitors (BRAFi). In preliminary work, we found striking up-regulation of AR expression in response to BRAFi, proliferation and tumorigenesis of BRAFi resistant melanoma cells are suppressed by AR inhibition, AR overexpression is by itself sufficient to confer BRAFi resistance. In further studies we will assess to what extent suppression of AR expression and activity has an impact on melanoma cell subpopulations with intrinsic BRAFi resistance and/or BRAFi-induced epigenetic reprogramming. We will analyze a collection of freshly derived cells from Patient- Derived Xenografts (PDX) of BRAFi sensitive and resistant melanomas and assess to what extent the beneficial effects of suppression of AR signalling occur in vivo, restoring one or more aspects of the BRAFi response of the corresponding PDXs.