Abstract Small cell lung cancer and large cell neuroendocrine carcinoma are classified as high-grade neuroendocrine tumors of the lung, representing extremely aggressive, life-threatening cancers with limited treatment options among various lung cancers. In these cancers, amplification of MYC family transcription factors: c-MYC, L-MYC and N-MYC is found to be mutually exclusive and overall account for ∼20%. In addition, recent studies have reported that L-MYC and c-MYC control lineage plasticity across molecular subtypes of small cell lung cancer defined by lineage-specific transcription factors such as ASCL-1 and NEUROD-1. Compared with L-MYC and c-MYC, the role of N-MYC, a lineage factor highly expressed in several tumors derived from neural cell lineages and a subset of neuroendocrine lung cancers, have not been described clearly. In this study, we aimed to investigate the role of N-MYC as a lineage-specific factors in neuroendocrine lung cancers. First, we investigated N-MYC binding profiles in N-MYC-high neuroendocrine lung cancer cell lines and found that genes related to neural cell differentiation were enriched in genes near N-MYC bound regions. Next, examination of genome-wide Myc-accessible regions in neuroendocrine lung cancer cell lines revealed that a fraction of peaks that overlapped between N-MYC- and c-MYC-classified cells, suggesting common functional binding of N-MYC and c-MYC. When we overexpressed N-MYC in L-MYC- or c-MYC-classified cells, expression profiles of the neuroendocrine lineage factors did not change, which was different from the previous findings on the relationships between L-MYC and c-MYC. Our findings suggest that N-MYC regulates distinct transcriptional program among the MYC family members although N-MYC and c-MYC share common binding profile. Citation Format: Hiroki Yamamoto, Takashi Sato, Yuri Yagami, Ryosuke Inoue, Hiromi Matsuo, Hideo Watanabe, Naoki Katsuhiko. Investigation of the role of N-MYC in lung neuroendocrine carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4761.
Yamamoto et al. (Fri,) studied this question.