A novel role for Neurog2 in MYCN driven neuroendocrine plasticity of prostate cancer

Abstract

SummaryNeuroendocrine prostate cancer (NEPC) presents a formidable clinical challenge owing to its aggressive progression and resistance to conventional therapies. A key driver of NEPC is the overexpression ofMYCN, a well-established oncogene associated with neuroendocrine tumors. However, efforts to directly inhibit the N-Myc protein encoded by this gene have resulted in limited success, thereby hindering therapeutic advancements. To overcome this obstacle, we conducted unbiased genome-wide screening using isogenic prostate cancer cell lines to identify the synthetic vulnerabilities ofMYCN. Among the identified candidates,NEUROG2emerged as a significant candidate. Neurog2 is a proneural transcription factor (PTF) known for its role in developmental processes and trans-differentiation of adult cells. Our findings demonstrate that Neurog2 depletion does not affect non-malignant cells, but significantly suppresses the growth ofMYCN-overexpressing cells and tumors in orthotopic NEPC models. Furthermore, our observations indicate that the Neurog2-mediated regulation of PTFs can facilitate NEPC development. Thus, targeting Neurog2 holds promise as an effective therapeutic strategy forMYCN-overexpressing NEPC.