2022 Spring Seminar Series Presents
DR. JASON SHELTZER
Assistant Professor, Yale School of Medicine, New Haven, CT
WHEN: Jan. 28, 2022, at Noon
WHEN: Seminar will be presented via Zoom
Please email Jacki Craig for the Zoom Link. Requests can be submitted any time before the Seminar but not after 11:00am the day of the seminar.
Off-target activity of targeted therapies undergoing clinical trials in cancer.
Overview: Ninety-seven percent 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 investigated 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 prolif- eration. 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.
Everyone is welcome to join the seminar, please email Jacki Craig to receive the Zoom link. Requests can be submitted any time before the seminar but not after 10:00am the day of the seminar.