Blind work
A group of researchers from the Cold Spring Harbor Laboratory, New York, has been working for the past few years to identify genes associated with low survival among cancer patients. In the course of this work, the researchers found that maternal embryonic leucine zipper kinase (MELK), often found in tumors in high concentrations, has absolutely no effect on cancer growth. This was striking, because dozens of scientific papers had previously identified MELK as a protein involved in cancer growth, which is extremely necessary for the survival of a cancer cell. However, when Jason Schelzer and his group turned off the production of MELK using CRISPR gene editing technology, the cancer cells did not die, they continued to exist.
To confirm their suspicions, the researchers conducted a large number of tests. After careful verification of these results, Schelzer's group was forced to conclude that MELK could not be a target for cancer treatment, as previously thought.
Together with researchers Ann Lin and Chris Giuliano, Schelzer described in detail that the mechanism of action of ten anticancer drugs was mistakenly associated with MELK and other proteins. All of these ten drugs attacking MELK and other target proteins are currently undergoing clinical trials with approximately 1,000 cancer patients. And although the drugs, apparently, are still able to kill cancer cells, they do not do it quite the way the researchers thought.
The CRISPR gene editing method was preceded by the RNA interference method (RNAi), which allowed researchers to stop protein synthesis by preventing information from being read from a specific gene. But unlike CRISPR, which can completely destroy or remove the desired gene, RNAi technologies can only create interference. There is also the possibility that RNAi could disrupt the production of thousands of other proteins found in the human cell.
Shelzer and his colleagues suspected not only MELK, but also six other proteins that were considered promising, which these ten experimental drugs for the treatment of cancer are aimed at. Using more precise CRISPR technology, they decided to detect the so-called non-targeted effect of these drugs, which is actually involved in the death of cancer cells.
One of the ten drugs studied kills cancer cells, presumably by inhibiting the PBK protein. But Sheltzer found that the mechanisms of their action have nothing to do with what the developers assumed, and interaction with PBK has nothing to do with the death of cancer cells.
To find out the true antitumor mechanism of action, the group exposed cancer cells to a very high concentration of a PBK-targeted drug. The cells were then given enough time to develop drug resistance.
A cancer cell that accidentally acquires a genetic change that blocks the effectiveness of the drug survives after treatment. Having determined the changes that have occurred, it is possible to find out exactly how the drug killed cancer cells.
The researchers exposed various mutated cancer cells to the drug OTS964. Almost all strains (1-3 columns) were destroyed. The cancer cells continued to grow (purple) only when they mutated to resist the drug's ability to block CDK11 protein receptors. This proves that CDK11 is necessary for cancer growth. Source: CSHL.
The team found that the cancer cells developed resistance due to a mutation of a gene that encodes cyclin-dependent kinase CDK11. The gene was mutated in such a way that the drug could no longer interact with this protein. A number of other experiments have confirmed that the CDK11 protein is the true target of this drug and that many types of cancer are dependent on CDK11 expression.
The knowledge gained will help researchers develop even more effective drugs that will specifically target CDK11.
Many drugs that are undergoing clinical trials on cancer patients simply don't work. If evidence such as that obtained in this study were regularly collected before drugs were approved for human trials, cancer–stricken volunteers would receive effective treatment, and the percentage of successful clinical trials would be much higher - currently only 3% of anti-cancer drugs tested receive FDA approval.
Article by A. Lin et al. Off-target toxicity is a common mechanism of action of cancer drugs pending clinical trials published in the journal Science Translational Medicine.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on Cold Spring Harbor: Cancer drugs don't always work as intended, researchers warn.