한빛사논문
Vascular Medicine Institute, University of Pittsburgh, University of Pittsburgh Medical Center
Vinny Negi1,†, Jimin Yang1,†, Gil Speyer2, Andres Pulgarin1, Adam Handen1, Jingsi Zhao1, Yi Yin Tai1, Ying Tang1, Miranda K. Culley1, Qiujun Yu1, Patricia Forsythe1, Anastasia Gorelova1, Annie M. Watson1, Yassmin Al Aaraj1, Taijyu Satoh1,3, Maryam Sharifi-Sanjani1, Arun Rajaratnam1, John Sembrat4, Steeve Provencher5, Xianglin Yin6, Sara O. Vargas7, Mauricio Rojas8, Sébastien Bonnet5, Stephanie Torrino9, Bridget K. Wagner10, Stuart L. Schreiber10, Mingji Dai6, Thomas Bertero9, Imad Al Ghouleh1,‡, Seungchan Kim11,‡, Stephen Y. Chan1,‡,*
1Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA. 2Research Computing, Arizona State University, Tempe, AZ, USA. 3Department of Cardiovascular Medicine, Tohoku University of Graduate School of Medicine, 1-1 Seiryomachi, Aoba-ku, 980-8574 Sendai, Japan. 4Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA. 5Pulmonary Hypertension and Vascular Biology Research Group, Faculty of Medicine, Laval University, Quebec, QC, Canada. 6Department of Chemistry, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, IN, USA. 7Department of Pathology, Boston Children's Hospital, MA, USA. 8Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Ohio State University College of Medicine, Columbus, OH, USA. 9Université Côte d'Azur, CNRS, IPMC, Sophia-Antipolis, France. 10Department of Chemistry and Chemical Biology, Harvard University; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 11Prairie View A&M Univ, Prairie View, TX, USA.
*Corresponding author.
†These authors contributed equally to this work.
‡These authors contributed equally to this work.
Abstract
Cancer therapies are being considered for treating rare noncancerous diseases like pulmonary hypertension (PH), but effective computational screening is lacking. Via transcriptomic differential dependency analyses leveraging parallels between cancer and PH, we mapped a landscape of cancer drug functions dependent upon rewiring of PH gene clusters. Bromodomain and extra-terminal motif (BET) protein inhibitors were predicted to rely upon several gene clusters inclusive of galectin-8 (LGALS8). Correspondingly, LGALS8 was found to mediate the BET inhibitor–dependent control of endothelial apoptosis, an essential role for PH in vivo. Separately, a piperlongumine analog’s actions were predicted to depend upon the iron-sulfur biogenesis gene ISCU. Correspondingly, the analog was found to inhibit ISCU glutathionylation, rescuing oxidative metabolism, decreasing endothelial apoptosis, and improving PH. Thus, we identified crucial drug-gene axes central to endothelial dysfunction and therapeutic priorities for PH. These results establish a wide-ranging, network dependency platform to redefine cancer drugs for use in noncancerous conditions.
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