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Many cancer drugs aim at the wrong molecular targets

Analysis using CRISPR gene-editing technology suggests that drugs’ mechanism of action are misunderstood.

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Lung cancer cells dividing, coloured scanning electron micrograph (SEM).

Many cancer drugs seek to stop malignant cells, such as these lung-cancer cells, from proliferating.Credit: Anne Weston, EM STP, The Francis Crick Institute/Science Photo Library

Many experimental cancer drugs might be succeeding in unintended ways, finds a study that used CRISPR–Cas9 gene editing to investigate how such drugs interact with malignant cells.

An analysis of ten drugs — including seven now in clinical trials — found that the proteins they target are not crucial for the survival of cancer cells. The results could help to explain why many cancer drugs fail in clinical trials, says William Kaelin, a cancer researcher at the Dana–Farber Cancer Institute in Boston, Massachusetts. Still, he says, “I’m not terribly surprised by the findings.”

The results, published in Science Translational Medicine1 on 11 September, do not necessarily mean that the drugs will not work at all. Some might have shown signs of success in early trials because they are acting on other, unknown targets, says the study’s lead author, cancer geneticist Jason Sheltzer of Cold Spring Harbor Laboratory in New York.

But not knowing drugs’ true mode of action could limit their prospects, he adds. In some cases, scientists can link a therapy to a molecular marker that indicates how likely that drug is to work in a given person. Scientists can then use these markers to select clinical-trial participants who are likely to benefit from the therapy, boosting the chances that it will succeed in the tests used to seek regulatory approval.

This approach is not possible if the drug’s target is uncertain, Sheltzer says. And drugs with unknown targets could harm normal cells in addition to cancer cells, raising the risk of toxic side effects.

“It's hard enough to develop drugs when you know their mechanism of action,” says Kaelin. “It's really difficult when you don't know the mechanism of action.”

Missing the target

Sheltzer and his lab first stumbled onto the problem by accident: in search of a positive control for an experiment, they selected a well-studied protein thought to be important in breast-cancer cell division. But when the team used CRISPR–Cas9 to mutate the gene that controls production of the protein2, they found no effect on cancer-cell growth. “We wanted to know whether that was just kind of a one-off occurrence, or whether there were other genes like it in clinical trials,” he says.

The researchers then selected ten other drugs, targeting a total of six proteins, for further evaluation. The ten drugs have been used in 29 clinical trials that aim to enrol more than 1,000 people; their protein targets have been implicated in cancer-cell survival and proliferation in over 180 publications.

But much of the evidence in support of those targets came from a technique called RNA-interference (RNAi), which allows researchers to silence specific genes — but can sometimes affect the activity of other genes.

Sheltzer’s team used multiple methods to evaluate the relationship between the drugs' efficacy and their targets. They included CRISPR–Cas9, which disables genes in a different way — by editing them to create mutations in them. Some studies have suggested that CRISPR is more precise than RNAi, although it too can sometimes affect other genes.

Homing in

In each case, they found that the target of the ten experimental cancer drugs did not affect the growth of cancer cells grown in the laboratory, compared to controls. Furthermore, when the scientists used CRISPR to wipe out expression of proteins targeted by the drugs, the therapies still killed cancer cells. This suggests that the drugs’ effectiveness is not tied to their purported protein targets after all.

The team then examined one drug, OTS964, in more detail. They found that, although the drug had been developed to target one protein, it was exerting its effect on cancer cells through another ― CDK11, which is involved in cell division.

The findings do have limitations, notes study co-author Ann Lin, a cancer researcher at Stanford University in California. Her team′s experiments were carried out in cells grown in the lab, she notes. “It is possible that these drug targets are essential in human patients,” she says, and not in isolated cells.

And Kaelin says that there was little prior genetic data on the collection of drugs and targets that the team examined — making it hard to back up their value in mice or people. Other targets, with stronger evidence to back them up, would likely fare better, he says.

But Sheltzer hopes to use his results to track down other proteins, like CDK11, that could be exploited for new cancer treatments. “There is an unexplored world of cancer targets out there,” he says. “By using CRISPR and other technologies to examine these drugs, we might unlock new targets.”

References

  1. 1.

    Lin, A. et al. Sci. Transl. Med. 11, eaaw8412 (2019).

  2. 2.

    Lin, A., Giuliano, C. J., Sayles, N. M. & Sheltzer, J. M. eLife 6, e24179 (2017).

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