Treatment-induced neuroendocrine prostate cancer (tNEPC) is a highly aggressive, therapy-resistant subtype of prostate cancer, where up to 40% of cases have amplification of a genomic locus best known for containing the MYCN gene. Amplification of this genomic locus (referred to as MYCN amplification) is associated with disease aggression, treatment resistance and poor prognosis across cancer types, including neuroblastoma and tNEPC. To date, there are no therapies available for tNEPC patients outside of palliative care, who face a dismal 5-year survival rate of 12.5%. Therefore, a better understanding of the biology underpinning MYCNamplification is required to allow for the development of more targeted therapies.
Recent findings from our lab have identified novel transcripts transcribed from this amplified locus in tNEPC patient samples and cell models, encoding previously uncharacterized proteins. We have developed specific parallel reaction monitoring assays for sensitively detecting and quantifying these novel proteins in tNEPC cell lines and patient-derived xenografts. Preliminary studies using doxycycline-inducible overexpression systems suggest that these unique proteins modulate androgen receptor (AR) signalling, neuroendocrine differentiation, and therapy resistance, underscoring their active roles in biological processes central to the tNEPC phenotype. Additionally, cellular localisation studies revealed their distinct compartmentalisation, indicating differential roles in oncogenic signalling. Through protein interaction mapping via immunoprecipitation and mass spectrometry, we aim to clarify the distinct roles of these novel proteins in MYCN-amplified tumours. This work holds the potential to guide the development of targeted therapies that disrupt the oncogenic functions of these proteins, leading to improved treatment strategies for tNEPC patients.