Ladademstat effects on neuroendocrine, inflamed and mesenchymal gene expression patterns in small cell lung cancer subtypes

Background: Small cell lung cancer (SCLC) is a highly aggressive and lethal tumor. Rapid response to chemotherapy radiotherapy observed in the majority of patients, but most them relapse within 6 12 months. Despite recent addition immunotherapy front-line chemotherapy, improvements progression-free overall survival are modest, with deaths occurring year diagnosis. SCLC heterogeneous can be divided into 4 molecularly distinct subtypes based on expression transcription factors: SCLC-A (about 50%, characterized by high levels ASCL1), SCLC-N 23%, NEUROD1), SCLC-P (7%, POU2F3) SCLC-I or “inflamed,” accounting for about 20% defined absence all three factors an inflamed gene signature associated increased T-cell infiltration, interferon signaling epithelial-to-mesenchymal transition. Importantly, this has been better immune checkpoint inhibitor (ICI) therapies. LSD1 inhibition potently blocks progression activating Notch pathway promoting IFN-Type I MHC-Class expression, leading infiltration boosting activity ICI variety tumor models. Herein we explore effects PhII clinical stage iadademstat both viability pattern lines from subtypes, special focus neuroendocrine inflamed/mesenchymal signatures. Materials Methods: Gene was assessed NCI-H510A, NCI-H146, NCI-H82, NCI-H446, NCI-H211, NCI-H526, NCI-H196 DMS114 after days treatment (AKA ORY-1001). A panel neuroendocrine, signaling, adaptive innate immunity mesenchymal genes evaluated drug. The residual also treatment. Results: Iadademstat strongly reduced as monotherapy marginally affecting other sub-types. activation repression upregulation, together upregulation native immunity-related particularly evident group. Mesenchymal “inflamed” were up-regulated Conclusions: at cell-autonomous level induces therapies others subtypes. These results support exploring combination inhibitors control tumorigenic drivers enhance SCLC. Conflict interest: Other Substantive Relationships: Natalia Sacilotto, Michele Lufino, Sarai Pacheco, Cristina Mascaró, Robert Soliva, Jordi Xaus employees Oryzon Genomics.