TAS1440, an LSD1 Inhibitor, Disrupts the INSM1-LSD1 Complex to Activate Tumor-Suppressive Pathways via Transcriptional Reprogramming in Neuroendocrine SCLC [RNA-seq]

Small cell lung cancer (SCLC) is characterized by aggressive progression and limited treatment options, necessitating novel therapeutic strategies. Lysine-specific histone demethylase 1A (LSD1), a key epigenetic enzyme essential for maintaining the neuroendocrine phenotype, represses NOTCH and TGF-ß signaling. Reactivation of these pathways suppresses proliferation and induces differentiation, underscoring LSD1's potential as a therapeutic target. However, the molecular mechanisms underlying LSD1 inhibition and chemoresistance drivers remain poorly understood. Here, through structure-based engineering, we developed TAS1440, a potent histone H3-competitive LSD1 inhibitor designed to enhance specificity and reduce off-target effects. Unlike covalent inhibitors, which bind irreversibly to the FAD cofactor in LSD1, TAS1440 non-covalently targets the histone H3-binding pocket, improving safety and efficacy. TAS1440 demonstrated superior anti-proliferative activity in SCLC-A cells with high INSM1 and ASCL1 expression. In xenograft models, TAS1440 achieved over 70% tumor growth inhibition with minimal toxicity, highlighting its potential for SCLC. Mechanistically, integrated studies revealed that TAS1440 exerts dual mechanisms: direct inhibition of LSD1 enzymatic activity and disruption of LSD1-repressive complexes, thereby altering the histone modification landscape and activating transcription factors such as INSM1 and SMAD2. These actions coordinately reprogram tumor-suppressive pathways, including TGF-ß and NOTCH signaling, positioning TAS1440 as an effective epigenetic therapy for SCLC. Importantly, Loss of LSD1 enzymatic activity and INSM1 knockout abrogated TAS1440's effects, elucidating its mechanism of action and uncovering potential resistance pathways. These findings establish TAS1440 as a next-generation LSD1 inhibitor with dual actions on transcriptional regulation and epigenetic reprogramming. TAS1440 holds significant promise as a targeted therapy for SCLC, particularly for the SCLC-A subtype with high INSM1 expression. Overall design: To study the transcriptional signatures and the effects of the LSD1 inhibitors in SCLC cell lines, we sequenced the bulk RNA of the 22 SCLC cell lines under DMSO/LSD1 inhibitors treatment. To elucidate whether the TAS1440-dependent dissociation of INSM1 from the LSD1 complex is crucial for inhibition of cell growth, we established NCI-H1417 and NCI-H146 cells lacking INSM1 using the CRISPR/Cas9 system. We then sequenced NCI-H1417 and NCI-H146 cells lacking INSM1 under DMSO/TAS1440 treatment.