Cancer drugs don’t always work as we want

In a new study, researchers have identified 10 cancer drugs currently in clinical trials that do not work how clinicians thought they would.

In identifying what went wrong, experts can now work to improve drug discovery and personalized medicine.

The research was conducted by a team at Cold Spring Harbor Laboratory (CSHL)

The team has been working to identify genes tied to low survival rates among cancer patients.

During this work, the researchers discovered that MELK, a protein often found in high levels in tumors, has absolutely no influence on cancer growth.

This was surprising because dozens of academic papers had previously identified MELK as cancer “addiction”—something absolutely essential for a cancer cell’s survival.

After rigorously checking and rechecking their results, the team had to conclude that MELK is not the ideal cancer drug target it was touted to be.

At the time, the team warned research and medical communities that this may be a common problem, leading to any number of promising cancer drugs being mischaracterized.

But to confirm their suspicions the researchers had to run a lot more tests.

In a new research paper, the team detailed how the “mechanism of action” of the 10 drugs was mischaracterized, just like MELK.

All 10 of the drugs are currently being tested in clinical trials and involve about 1000 human cancer patients.

And while they do appear capable of killing cancer cells, it’s just not in the way researchers had thought.

Prior to CRISPR gene editing, the technique that most scientists used to interfere with the production of a specific protein was called RNA interference (RNAi).

The method allowed researchers to prevent the instructions for producing a protein made by any one gene to be read by a cell.

But unlike CRISPR, which can completely break or remove a specific gene, RNAi technologies only run interference.

There is also the chance that the process will covertly interfere with the production of one of the thousands of other proteins found in a human cell.

That’s what the team suspected was happening not only with MELK but with the six other promising proteins targeted by those ten experimental cancer drugs.

Something was also being affected, and it was this off-target effect that was truly stopping cancer. Using the more accurate CRISPR technology, this was what the team set out to discover.

To do this, they took one of the 10 drugs—in this case, one which kills cancer cells by supposedly inhibiting the protein PBK. But Sheltzer found it was doing something very different.

To find out the true anti-cancer mechanism of action, the team exposed cancer cells to “a very, very high concentration” of the PBK-targeting drug.

The researchers then gave the cells plenty of time to develop drug resistance.

The team found that the cancer cells evolved their resistance by mutating the gene that produces the protein CDK11.

The gene was mutated in such a way that the drug can no longer interact with it, much like a rusty gate may no longer lock with its key.

Along with some other confirmatory experiments, this told the team that CDK11 is the true mechanism of action against cancer.

Armed with this knowledge, the researchers now hope to design even better drugs that target CDK11 more specifically.

The study is published in the journal Science Translational Medicine.

Copyright © 2019 Knowridge Science Report. All rights reserved.