A preclinical platform for assessing antitumor effects and systemic toxicities of cancer drug targets

Li, Xiang, Huang, Chun-Hao, Sánchez-Rivera, Francisco J, Kennedy, Margaret C, Tschaharganeh, Darjus F, Morris, John P, Montinaro, Antonella, O'Rourke, Kevin P, Banito, Ana, Wilkinson, John E, Chen, Chi-Chao, Ho, Yu-Jui, Dow, Lukas E, Tian, Sha, Luan, Wei, de Stanchina, Elisa, Zhang, Tinghu, Gray, Nathanael S, Walczak, Henning, Lowe, Scott W (April 2022) A preclinical platform for assessing antitumor effects and systemic toxicities of cancer drug targets. Proceedings of the National Academy of Sciences of USA, 119 (17). e2110557119. ISSN 0027-8424

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Abstract

SignificanceMany new cancer drugs fail at the clinical stage owing to poor efficacy and/or excessive toxicity, though whether this reflects shortcomings of the target or the drug is often unclear. To gain earlier insights into factors that can influence the therapeutic index of target inhibition in vivo, we combine inducible RNA interference and somatic engineering technologies to produce a cost-effective platform that enables systemic and inducible suppression of candidate target in normal tissues and tumor cells in the same mouse. By comparing the consequences of genetic and pharmacological CDK9 inhibition, we establish the utility of this platform to predict factors influencing the therapeutic index. Additionally, our studies provide support, and some cautionary notes, for the clinical development of CDK9 inhibitors.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > neoplasms bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNAi organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase diseases & disorders > cancer > cancer types > liver cancer organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organism description > animal > mammal > rodent
CSHL Authors:	Lowe, Scott W.
Communities:	CSHL labs > Lowe lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	26 April 2022
Date Deposited:	02 May 2022 20:06
Last Modified:	11 Jan 2024 21:18
PMCID:	PMC9169916
URI:	https://repository.cshl.edu/id/eprint/40600

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