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Bioinformatics Data Mining Repurposes the JAK2 (Janus Kinase 2) Inhibitor Fedratinib for Treating Pancreatic Ductal Adenocarcinoma by Reversing the KRAS (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog)-Driven Gene Signature

by Li-Wei Liu 1,†, Yao-Yu Hsieh 2,3,† and Pei-Ming Yang 4,5,6,7,*
1
School of Nutrition and Health Sciences, Taipei Medical University, Taipei 11031, Taiwan
2
Division of Hematology and Oncology, Taipei Medical University Shuang Ho Hospital, New Taipei City 23561, Taiwan
3
Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
4
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
5
Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
6
TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
7
Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
*
Author to whom correspondence should be addressed.
These authors contribute equally to this work.
J. Pers. Med. 2020, 10(3), 130; https://doi.org/10.3390/jpm10030130
Received: 26 July 2020 / Revised: 1 September 2020 / Accepted: 15 September 2020 / Published: 16 September 2020
Pancreatic ductal adenocarcinoma (PDAC) is still one of the most aggressive and lethal cancer types due to the late diagnosis, high metastatic potential, and drug resistance. The development of novel therapeutic strategies is urgently needed. KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) is the major driver mutation gene for PDAC tumorigenesis. In this study, we mined cancer genomics data and identified a common KRAS-driven gene signature in PDAC, which is related to cell–cell and cell–extracellular matrix (ECM) interactions. Higher expression of this gene signature was associated with poorer overall survival of PDAC patients. Connectivity Map (CMap) analysis and drug sensitivity profiling predicted that a clinically approved JAK2 (Janus kinase 2)-selective inhibitor, fedratinib (also known as TG-101348), could reverse the KRAS-driven gene signature and exhibit KRAS-dependent anticancer activity in PDAC cells. As an approved treatment for myelofibrosis, the pharmacological and toxicological profiles of fedratinib have been well characterized. It may be repurposed for treating KRAS-driven PDAC in the future. View Full-Text
Keywords: bioinformatics; drug repurposing; gene signature; histone deacetylase inhibitor; pancreatic ductal adenocarcinoma bioinformatics; drug repurposing; gene signature; histone deacetylase inhibitor; pancreatic ductal adenocarcinoma
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Liu, L.-W.; Hsieh, Y.-Y.; Yang, P.-M. Bioinformatics Data Mining Repurposes the JAK2 (Janus Kinase 2) Inhibitor Fedratinib for Treating Pancreatic Ductal Adenocarcinoma by Reversing the KRAS (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog)-Driven Gene Signature. J. Pers. Med. 2020, 10, 130.

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