Are Drugmakers Going After the Right Targets in Cancer Cells?
Targeting plays a significantly important role in the fight against cancer, and many drugs that have been aimed at specific proteins in cancer cells may not work as initially designed. However, new research may provide a clue of where drug designers can look for potential cancer-killing solutions.
Researchers from Cold Spring Harbor Laboratory in New York discovered that certain proteins thought essential for the survival of cancer cells – the same proteins that many drugmakers have been targeting – may not be as important after all. For example, at one point, the protein MELK had been considered important for some forms of breast cancer to proliferate and became the target of some drugs in development. The Cold Spring Harbor researchers used CRISPR to remove MELK from cancer cells and discovered that the “cancer cells didn’t care whatsoever,” Jason Sheltzer, a cancer biologist at Cold Spring Harbor Lab told The New York Times.
A gene thought essential to the survival of that cancer cell did not stop it from growing. What’s more, when the researchers in Sheltzer’s lab went ahead and attacked the cancer cells with the MELK-targeting drug, which was not disclosed in the article, the cancer cells were killed despite the lack of the MELK protein.
Sheltzer, as the Times reported, expanded his experiment to include other drugs that targeted different proteins in cancer cells. Every time the researchers used CRISPR-Cas9 to remove the protein from the cancer cell and then attacked it with the targeted drugs, the cancer cells were destroyed -- again, regardless of the fact that the “essential” protein had already been removed. Sheltzer said this leads to the question of whether or not drug designs are on target or not.
Sheltzer and his team published their findings in the journal Science Translational Medicine. In the article, the researchers point to the fact that 97% of drug-indication pairs tested in clinical oncology trials are never approved. That number is supported by data from a report earlier this year that showed only 3% of oncology drugs in clinical trials from 2000 to 2015 were approved by the U.S. Food and Drug Administration.
The Cold Spring Harbor team’s data showed that “contrary to previous reports obtained predominantly with RNA interference and small-molecule inhibitors,” the proteins that had been targeted by the drugs used in the experiment were not essential 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,” Sheltzer and his team said in the report.
While MELK and the other proteins may not have been as important to the proliferation of the cancer cells, continued experiments may have found one that is essential. Using a drug known as OTS964 that was at their disposal, the researches targeted a number of different cancer cells. They discovered that OTS964, a CDK11 inhibitor, killed the cancer cells. Those that did not survive were examined to see what was inside the cells. DNA sequencing of those surviving cells showed they each had a mutated form of the protein CDK11B, which OTS964 could not touch. When they specifically cut out that protein from the cells using CRISPR, and then applied the drugs, the cancer cells died.
“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,” the researchers wrote.
Sheltzer told the Times that it may behoove researchers to focus on mutations of proteins in order to ensure greater success in developing cancer treatments.
“There is probably a whole universe of unexplored drug targets in the cancer cell,” Sheltzer told the Times.