fig1

Figure 1. Schematics of the main mechanisms linked to the development of resistance to androgen deprivation therapy and androgen receptor (AR)-targeted therapies in prostate cancer. Genomic rearrangements and mutations in the AR locus or its cofactors restore AR signaling promoting tumor growth. Alternatively, tumor cells transition towards an alternative AR-independent lineage showing neuroendocrine phenotype [neuroendocrine prostate cancer (NEPC)] in the setting of MYCN amplification and/or RB1 and TP53 loss. Tumors cells showing neither activation of the AR program nor neuroendocrine markers (DNPCs, double negative prostate cancer) show activation of the FGFR-MAPK pathway. Alternative pathways that promote tumor growth independently of AR include a gastrointestinal (GI) circuit controlled by specific master transcription factors and the WNT pathway. Enh: enhancer; NTD: N-terminal transactivation domain; DBD: DNA-binding domain; LBD: ligand-binding domain