Open AccessA preclinical platform for assessing antitumor effects and systemic toxicities of cancer drug targets
Author(s) -
Xiang Li,
ChunHao Huang,
Francisco J. SánchezRivera,
Margaret C. Kennedy,
Darjus F. Tschaharganeh,
John P. Morris,
Antonella Montinaro,
Kevin P. O’Rourke,
Ana Banito,
John E. Wilkinson,
Chi-Chao Chen,
Yu-Jui Ho,
Lukas E. Dow,
Sha Tian,
Wei Luan,
Elisa de Stanchina,
Tinghu Zhang,
Nathanael S. Gray,
Henning Walczak,
Scott W. Lowe
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2110557119
Subject(s) - doxycycline , in vivo , pharmacology , drug , cancer , drug development , toxicity , cancer cell , cancer research , medicine , biology , antibiotics , microbiology and biotechnology
Significance Many 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.