Li, Xiang ORCID: 0000-0001-7422-251X, Huang, Chun-Hao, Sanchez-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 and Lowe, Scott W. (2022). A preclinical platform for assessing antitumor effects and systemic toxicities of cancer drug targets. Proc. Natl. Acad. Sci. U. S. A., 119 (17). WASHINGTON: NATL ACAD SCIENCES. ISSN 1091-6490

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Abstract

Anticancer drug development campaigns often fail due to an incomplete understanding of the therapeutic index differentiating the efficacy of the agent against the cancer and its on-target toxicities to the host. To address this issue, we established a versatile pre clinical platform in which genetically defined cancers are produced using somatic tissue engineering in transgenic mice harboring a doxycycline-inducible short hairpin RNA against the target of interest. In this system, target inhibition is achieved by the addition of doxycycline, enabling simultaneous assessment of efficacy and toxicity in the same animal. As proof of concept, we focused on CDK9-a cancer target whose clinical development has been hampered by compounds with poorly understood target specific-ity and unacceptable toxicities. We systematically compared phenotypes produced by genetic Cdk9 inhibition to those achieved using a recently developed highly specific small molecule CDK9 inhibitor and found that both perturbations led to robust antitumor responses. Remarkably, nontoxic levels of CDK9 inhibition could achieve signifi- cant treatment efficacy, and dose-dependent toxicities produced by prolonged CDK9 suppression were largely reversible upon Cdk9 restoration or drug withdrawal. Overall, these results establish a versatile in vivo target validation platform that can be employed for rapid triaging of therapeutic targets and lend support to efforts aimed at advancing CDK9 inhibitors for cancer therapy.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Li, XiangUNSPECIFIEDorcid.org/0000-0001-7422-251XUNSPECIFIED
Huang, Chun-HaoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sanchez-Rivera, Francisco J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kennedy, Margaret C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tschaharganeh, Darjus F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morris, John P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Montinaro, AntonellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
O'Rourke, Kevin P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Banito, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wilkinson, John E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, Chi-ChaoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ho, Yu-JuiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dow, Lukas E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tian, ShaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luan, WeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Stanchina, ElisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhang, TinghuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gray, Nathanael S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walczak, HenningUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lowe, Scott W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-693236
DOI: 10.1073/pnas.2110557119
Journal or Publication Title: Proc. Natl. Acad. Sci. U. S. A.
Volume: 119
Number: 17
Date: 2022
Publisher: NATL ACAD SCIENCES
Place of Publication: WASHINGTON
ISSN: 1091-6490
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DEPENDENT KINASE INHIBITOR; R-ROSCOVITINE; PHASE-II; CDK9; TRANSCRIPTION; GENE; MICE; FLAVOPIRIDOL; SUPPRESSION; ELONGATIONMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69323

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