Targeting NOTCH activation in small cell lung cancer through LSD1 inhibition

Abstract

Small cell lung cancer (SCLC) is a recalcitrant, aggressive neuroendocrine-type cancer for which little change to first-line standard-of-care treatment has occurred within the last few decades. Unlike nonsmall cell lung cancer (NSCLC), SCLC harbors few actionable mutations for therapeutic intervention. Lysine-specific histone demethylase 1A (LSD1 also known as KDM1A) inhibitors were previously shown to have selective activity in SCLC models, but the underlying mechanism was elusive. Here, we found that exposure to the selective LSD1 inhibitor ORY-1001 activated the NOTCH pathway, resulting in the suppression of the transcription factor ASCL1 and the repression of SCLC tumorigenesis. Our analyses revealed that LSD1 bound to the NOTCH1 locus, thereby suppressing NOTCH1 expression and downstream signaling. Reactivation of NOTCH signaling with the LSD1 inhibitor reduced the expression of ASCL1 and neuroendocrine cell lineage genes. Knockdown studies confirmed the pharmacological inhibitor-based results. In vivo, sensitivity to LSD1 inhibition in SCLC patient-derived xenograft (PDX) models correlated with the extent of consequential NOTCH pathway activation and repression of a neuroendocrine phenotype. Complete and durable tumor regression occurred with ORY-1001–induced NOTCH activation in a chemoresistant PDX model. Our findings reveal how LSD1 inhibitors function in this tumor and support their potential as a new and targeted therapy for SCLC.

Precision medicine for human cancers with Notch signaling dysregulation (Review)

“…Oncogenic Notch signaling is activated in NScLc owing to GoF NOTCH1 mutations or ELF3-dependent NOTCH3 upregulation (66,73), whereas tumor-suppressive Notch signaling is inactivated in ScLc owing to LoF NOTCH1 mutations or epigenetic NOTCH1 repression (72,77). In HNScc, tumor-suppressive Notch signaling is inactivated owing to LoF NOTCH1 mutations, but oncogenic Notch signaling is activated by JAG1, JAG2 or NOTCH3 upregulation (69,89).…”

A NOTCH1/LSD1/BMP2 Co-Regulatory Network Mediated by miR-137 Negatively Regulates Osteogenesis of Human Adipose-Derived Stem Cells

“…Collectively, we brought insight into how the NOTCH1-HES1 pathway was regulated by miR-137. LSD1 has been linked to the repression of NOTCH1 pathway in various cell types [45,[59][60][61][62][63], though one study states that it functions as a corepressor when associated with RBPJ-repressor complex and as a NOTCH1 coactivator upon NOTCH activation [64]. Nevertheless, few studies have reported the interplay between NOTCH1 and LSD1 during the osteogenesis of hASCs and whether this interaction contributes to the osteogenic regulation of miR-137 is still unknown.…”

“…NOTCH1 has emerged as a target of miR-137 in human renal mesangial cells [40], retinal ganglion cells [41], neurons [42], non-small cell lung cancer cells [43] and breast cancer cells [44], but whether it is directly inhibited by miR-137 has not yet been identi ed in hASCs. In small cell lung cancer cells, NOTCH1 pathway is activated by LSD1 inhibitor and suppressed due to the binding of LSD1 [45]. Additionally, the induction of NOTCH signal impairs the activation of BMP pathway and the osteoblastic differentiation of dental follicle cells [46].…”

Updates on the Role of Molecular Alterations and NOTCH Signaling in the Development of Neuroendocrine Neoplasms

“…This inhibitor activates NOTCH pathway, inhibiting consequently the transcription factor ASCL1 and the repression of the tumorigenesis and the neuroendocrine phenotype in this type of tumours. A complete and long-term tumour regression was obtained after treating with ORY-1001 SCLC patient-derived xenograft (PDX) mice models [98]. Thus, this inhibitor has been suggested as a potential new targeted therapy for SCLC.…”