Some experimental cancer drugs kill by off-target effects

By Marilynn Larkin

NEW YORK (Reuters Health) - 18/9/2019

Some cancer drug candidates in clinical trials kill tumor cells through off-target effects, rather than by interacting with their intended target, researchers say.

"Most new oncology drugs fail during clinical trials in cancer patients. In fact, up to 97% of drug-indication pairs that enter clinical trials in cancer never receive FDA approval," Dr. Jason Sheltzer of Cold Spring Harbor Laboratory in New York told Reuters Health by email. "Our work identifies a set of factors that we believe contributes to this extremely high failure rate."

"We found that many anti-cancer drugs have been designed to inhibit proteins with no detectable role in cancer growth," he said. "Furthermore, the drugs used to target those proteins only kill cancer cells through an off-target effect."

Dr. Sheltzer and colleagues used CRISPR-Cas9 mutagenesis technology to investigate 10 cancer drug candidates and drug targets in various stages of clinical testing. The drugs target one of six proteins that have been identified as important for cancer cell survival in more than 180 publications, and have been used in at least 29 clinical trials involving more than 1,000 patients, according to their Science Translational Medicine study, online September 11.

"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," the authors state. "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."

The team's tests included candidates such as citrinostat and ricolinostat, which are being tested against multiple myeloma.

Dr. Sheltzer said, "Clinicians should be aware that many experimental drugs may have an incorrect mechanism-of-action. We are following up with one drug in particular, OTS964. (As noted in the study), this drug was previously believed to be an inhibitor of a protein called PBK. Using CRISPR, we showed that PBK was actually dispensable for cancer growth."

"We did a series of experiments that demonstrated that OTS964 is actually an inhibitor of a different protein, called CDK11," he said. "This is the first inhibitor of CDK11 that has ever been found. We're now doing follow-up experiments to explore CDK11 as a potential new drug target."

"Stringent genetic validation - in particular, through the use of new CRISPR gene editing technology - can improve how new drug targets are characterized and will decrease the number of drugs that are tested in cancer patients but fail to provide any benefit," he concluded.

Hematologist-oncologist Dr. Vinay Prasad of Oregon Health and Science University in Portland called the study "provocative."

"The glaring weakness of the paper is that all of these drugs are in testing and not approved," he commented in an email to Reuters Health. "If the authors were to take approved cancer drugs and replicate this analysis for those drugs, it would be extremely provocative. Until they are approved, we do not know if the (tested) drugs were destined to succeed or fail or come to the US market or not. It is possible they were all doomed."

"The authors of this paper are asking a very tough question," he said. "In the age of targeted drugs, how many actually work by hitting that target? Their results provide some caution, but if they repeat their study with 10 approved US cancer drugs, and find similar results, then a lot of us, myself included, will find our jaws on the floor."


Sci Transl Med 2019.

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