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<p>Neuroendocrine 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 of <i>MYCN</i>, 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 of <i>MYCN</i>. Among the identified candidates, <i>NEUROG2</i> emerged 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 of <i>MYCN</i>-overexpressing cells and tumors in orthotopic NEPC models. Furthermore, our observations indicate that Neurog2-driven modulation of PTFs potentially contribute to NEPC development. Thus, targeting Neurog2 holds promise as an effective therapeutic strategy for <i>MYCN</i>-overexpressing NEPC.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月29日

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  • Prachi Walke,
  • Jared D. W. Price,
  • Frederick S. Vizeacoumar,
  • Nickson Joseph,
  • Vincent Maranda,
  • Bari Chowdhury,
  • Jay Patel,
  • Yue Zhang,
  • He Dong,
  • Lara New,
  • Ashtalakshmi Ganapathysamy,
  • Li Hui Gong,
  • Mary Lazell-Wright,
  • Hussain Elhasasna,
  • Kalpana K. Bhanumathy,
  • Yuliang Wu,
  • Yuzhuo Wang,
  • Andrew Freywald,
  • Anand Krishnan,
  • Franco J. Vizeacoumar

摘要

Neuroendocrine 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 of MYCN, 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 of MYCN. Among the identified candidates, NEUROG2 emerged 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 of MYCN-overexpressing cells and tumors in orthotopic NEPC models. Furthermore, our observations indicate that Neurog2-driven modulation of PTFs potentially contribute to NEPC development. Thus, targeting Neurog2 holds promise as an effective therapeutic strategy for MYCN-overexpressing NEPC.