1. Jumonji histone demethylases are therapeutic targets in small cell lung cancer.
- Author
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Nguyen A, Nuñez CG, Tran TA, Girard L, Peyton M, Catalan R, Guerena C, Avila K, Drapkin BJ, Chandra R, Minna JD, and Martinez ED
- Subjects
- Animals, Humans, Mice, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Etoposide pharmacology, Etoposide therapeutic use, Repressor Proteins metabolism, Repressor Proteins genetics, Repressor Proteins antagonists & inhibitors, Xenograft Model Antitumor Assays, Basic Helix-Loop-Helix Transcription Factors metabolism, Basic Helix-Loop-Helix Transcription Factors genetics, Endoplasmic Reticulum Stress drug effects, Jumonji Domain-Containing Histone Demethylases metabolism, Jumonji Domain-Containing Histone Demethylases antagonists & inhibitors, Jumonji Domain-Containing Histone Demethylases genetics, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Lung Neoplasms genetics, Lung Neoplasms metabolism, Small Cell Lung Carcinoma drug therapy, Small Cell Lung Carcinoma pathology, Small Cell Lung Carcinoma genetics, Small Cell Lung Carcinoma metabolism
- Abstract
Small cell lung cancer (SCLC) is a recalcitrant cancer of neuroendocrine (NE) origin. Changes in therapeutic approaches against SCLC have been lacking over the decades. Here, we use preclinical models to identify a new therapeutic vulnerability in SCLC consisting of the targetable Jumonji lysine demethylase (KDM) family. We show that Jumonji demethylase inhibitors block malignant growth and that etoposide-resistant SCLC cell lines are particularly sensitive to Jumonji inhibition. Mechanistically, small molecule-mediated inhibition of Jumonji KDMs activates endoplasmic reticulum (ER) stress genes, upregulates ER stress signaling, and triggers apoptotic cell death. Furthermore, Jumonji inhibitors decrease protein levels of SCLC NE markers INSM1 and Secretogranin-3 and of driver transcription factors ASCL1 and NEUROD1. Genetic knockdown of KDM4A, a Jumonji demethylase highly expressed in SCLC and a known regulator of ER stress genes, induces ER stress response genes, decreases INSM1, Secretogranin-3, and NEUROD1 and inhibits proliferation of SCLC in vitro and in vivo. Lastly, we demonstrate that two different small molecule Jumonji KDM inhibitors (pan-inhibitor JIB-04 and KDM4 inhibitor SD70) block the growth of SCLC tumor xenografts in vivo. Our study highlights the translational potential of Jumonji KDM inhibitors against SCLC, a clinically feasible approach in light of recently opened clinical trials evaluating this drug class, and establishes KDM4A as a relevant target across SCLC subtypes., (© 2024. The Author(s).)
- Published
- 2024
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