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

Autor:	Li X; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute, New York, NY 10065.; Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10021., Huang CH; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute, New York, NY 10065.; Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10021., Sánchez-Rivera FJ; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute, New York, NY 10065., Kennedy MC; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute, New York, NY 10065., Tschaharganeh DF; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute, New York, NY 10065., Morris JP 4th; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute, New York, NY 10065., Montinaro A; Centre for Cell Death, Cancer, and Inflammation, UCL Cancer Institute, University College London, London WC1E 6DD, United Kingdom., O'Rourke KP; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute, New York, NY 10065.; Weill Cornell Medicine/The Rockefeller University/Sloan Kettering Institute Tri-Institutional MD-PhD Program, New York, NY 10065., Banito A; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute, New York, NY 10065., Wilkinson JE; Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109., Chen CC; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute, New York, NY 10065.; Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10021., Ho YJ; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute, New York, NY 10065., Dow LE; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute, New York, NY 10065., Tian S; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute, New York, NY 10065., Luan W; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute, New York, NY 10065., de Stanchina E; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute, New York, NY 10065., Zhang T; Innovative Medicines Accelerator, Stanford Chemistry, Engineering & Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA 94305., Gray NS; Innovative Medicines Accelerator, Stanford Chemistry, Engineering & Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA 94305., Walczak H; Centre for Cell Death, Cancer, and Inflammation, UCL Cancer Institute, University College London, London WC1E 6DD, United Kingdom.; Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cluster of Excellence, University of Cologne, Cologne 50931, Germany.; Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany., Lowe SW; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute, New York, NY 10065.; Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10021.; Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Apr 26; Vol. 119 (17), pp. e2110557119. Date of Electronic Publication: 2022 Apr 20.
DOI:	10.1073/pnas.2110557119
Abstrakt:	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 preclinical 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 specificity 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 significant 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.
Databáze:	MEDLINE
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