Abstract
Small cell lung cancer (SCLC) is aggressive with limited treatment options, requiring new therapies. Lysine-specific histone demethylase 1 A (LSD1) maintains neuroendocrine state by repressing NOTCH/TGF-β signaling; their reactivation suppresses proliferation and induces differentiation. However, mechanisms of LSD1 inhibition and chemoresistance remain unclear. Here we developed TAS1440, a histone H3-competitive LSD1 inhibitor, using structure-based engineering to improve specificity and reduce off-target effects. Unlike irreversible inhibitors targeting the flavin adenine dinucleotide site, TAS1440 non-covalently targets the H3-binding pocket to enhance safety and efficacy. TAS1440 suppressed proliferation in INSM1/ASCL1-high SCLC-A cells and induced tumor regression in xenografts. TAS1440 acts through dual mechanisms: inhibiting LSD1 activity and disrupting LSD1-repressive complexes, remodeling histone marks and activating transcription factors INSM1 and SMAD2. These actions reprogram tumor-suppressive TGF-β/NOTCH signaling, supporting TAS1440 as epigenetic therapy for SCLC. Loss of LSD1 enzymatic activity or INSM1 knockout abrogated TAS1440 effects, defining its mode of action and chemoresistance. These findings support TAS1440 as a next-generation epigenetic therapy candidate for INSM1-high SCLC-A.
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Data availability
Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. The RNA-seq data generated in this study have been deposited in the Gene Expression Omnibus (GEO) database under accession code GSE272002, and the ChIP-seq data generated in this study have been deposited in the GEO database under accession code GSE272003. The mass spectrometry proteomics data were deposited in the Japan Proteome Standard repository/database JPST003190. Proteomics data supporting the findings of this study are available within the article and in Supplementary Data 1. Source data are provided with this paper.
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Acknowledgements
This study was funded by Taiho Pharmaceutical Co., Ltd., Japan, and was supported by Grants-in-Aid for Scientific Research KAKENHI, Scientific Research (B) cat. no. 19H03708, (C) cat. no. 20K08397, (B) cat. no. 21H02974, (Pioneering) cat. no. 23K17429, (C) cat. no. 19K07635, and (C) cat. no. 18K07439. This work was partly supported by the Takeda Science Foundation, the Naito Foundation, the Novartis Foundation (Japan), the Cell Science Research Foundation, the Princess Takamatsu Cancer Research Fund, the Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care, the Hamaguchi Biochemistry Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Yamaguchi Endocrine Foundation, and the Donated Fund of Next Generation Hormone Academy for Human Health and Longevity.
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T.Ma. conceived the study. T.T. contributed to the conceptualization and study design, developed the methodology, acquired funding, and provided project administration and resources. S.O. provided project administration and resources, supervised the study, and reviewed and edited the manuscript. T.Ma., Y.G., S.T., A.O., A.N., N.H., T.O., T.Mi., S.Y., T.S., R.H., and Y.Ko. analyzed and interpreted the data. Y.Ka., O.O. performed the proteomic analyses. T.S. contributed to methodology and data visualization. Y.G. performed the animal, cell-based, protein and RNA experiments. S.T., H.Y., and M.C. performed cell-based experiments. T.F. performed cell immunostaining and animal experiments. A.N., R.K., Y.U., H.S., M.Y., and I.S. performed animal experiments. M.N. generated the plasmid constructs. S.Y., T.S., R.H., and Y.Ko. performed additional investigations. T.Ma., S.T., A.N., N.H., T.F., Y.T., T.K., S.Y., and Y.Ko. validated the findings. T.Ma., Y.G., S.T., A.O., A.N., N.H., T.S., R.H., and Y.Ko. prepared the figures and visualized the data. T.Ma., Y.G., A.O., N.H., and T.F. drafted the manuscript. Y.G., A.O., N.H., R.K., and S.M. reviewed and edited the manuscript. All authors approved the final manuscript.
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None of the authors affiliated with Chiba University (Yingbo Gong, Atsushi Onodera, Akitoshi Nakayama, Naoko Hashimoto, Takahiro Fuchigami, Motoi Nishimura, Tomohiro Ogino, Ryota Kurimoto, Yasufumi Uematsu, Hidemi Suzuki, Hongye Yu, Mingyang Chen, Masataka Yokoyama, Ikki Sakuma, Yuki Taki, Takashi Kono, Takashi Miki, Shinichiro Motohashi, and Tomoaki Tanaka) have any competing interests. None of the authors affiliated with Kazusa DNA Research Institute (Yusuke Kawashima and Osamu Ohara) have any competing interests. Takumitsu Machida, Sayaka Tsukioka, Satoshi Yamashita, Tatsuya Suzuki, Ryo Hatanaka, Yasuo Kodama, and Shuichi Ohkubo are full-time employees of Taiho Pharmaceutical Co., Ltd.
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Machida, T., Gong, Y., Tsukioka, S. et al. LSD1 inhibitor, TAS1440, disrupts INSM1-LSD1 complex activating tumor-suppressive pathways via transcriptional reprogramming in neuroendocrine SCLC. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70984-1
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DOI: https://doi.org/10.1038/s41467-026-70984-1
