HiTS Seminar: Jason Sheltzer, 10:00 AM, Thursday, January 16, 2020
Cold Spring Harbor Laboratory, NY
Genetic approaches to improve the characterization of anti-cancer drugs
97% of drug-indication pairs that are tested in clinical trials in oncology never advance to receive FDA approval. While lack of efficacy and dose-limiting toxicities are the most common causes of trial failure, the reason(s) why so many new drugs encounter these problems is not well understood. Using CRISPR-Cas9 mutagenesis, we are investigating a set of cancer drugs and drug targets in various stages of clinical testing. We show that—contrary to previous reports obtained predominantly with RNA interference and small-molecule inhibitors—the proteins ostensibly targeted by these drugs are nonessential for cancer cell proliferation. Moreover, the efficacy of each drug that we tested was unaffected by the loss of its putative target, indicating that these compounds kill cells via off-target effects. By applying a genetic target-deconvolution strategy, we found that the mischaracterized anticancer agent OTS964 is actually a potent inhibitor of the cyclin-dependent kinase CDK11 and that multiple cancer types are addicted to CDK11 expression. We suggest that stringent genetic validation of the mechanism of action of cancer drugs in the preclinical setting may decrease the number of therapies tested in human patients that fail to provide any clinical benefit. Additionally, we are investigating the role of CDK11 in cancer cell mitosis, in order to uncover whether a therapeutic window exists for inhibiting this kinase as an anti-cancer strategy.
10:00 am – 11:00 am
Thursday, January 16, 2020
Harvard Medical School
210 Longwood Avenue
Warren Alpert Building 563
Boston, MA 02115
Hosted by Kenichi Shimada, Ph.D.