Targeting Notch Activation In Small Cell Lung Cancer Through Lsd1 Inhibition

Small cell lung cancer (SCLC) is a recalcitrant, lethal tumor type for which little change to first-line standard-of-care treatment has been made over the last few decades. Unlike non-small cell lung cancer (NSCLC), SCLC harbors few actionable mutations for therapeutic intervention. Activation of NOTCH signaling impairs neuroendocrine differentiation and suppresses SCLC, but there are no therapeutic strategies to activate NOTCH in SCLC. LSD1 inhibitors were previously shown to have selective activity in SCLC models, but the underlying mechanism was unknown. Here we demonstrate that exposure to the highly potent and selective LSD1 inhibitor, RG6016/ORY1001, induces NOTCH pathway activation, resulting in the suppression of ASCL1, a regulator of neuroendocrine cell state critical for SCLC oncogenesis. LSD1 binds to the NOTCH1 locus, modulating NOTCH1 expression in SCLC cells. In vivo, sensitivity to LSD1 inhibition in SCLC patient-derived xenograft (PDX) models correlates with the extent of NOTCH pathway activation and repression of a neuroendocrine phenotype. LSD1 inhibition represents a novel therapeutic approach to target the activation of NOTCH and suppression of ASCL1 in SCLC. Citation Format: Arnaud Augert, Emily Eastwood, Ali H. Ibrahim, Nan Wu, Eli Grunblatt, Ryan Basom, Keith D. Eaton, Renato Martins, John Poirier, Charles M. Rudin, Francesca Milletti, Fiona Mack, David MacPherson. Targeting NOTCH activation in small cell lung cancer through LSD1 inhibition [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B08.