BIOMEDICINE
CRISPR reveals some cancer drugs hit unexpected targets
Method that generated drug leads may be flawed
Frey says the decision was made “by mutual consent” because the two “find it too diffi- cult to embark on the new strategy with full conviction.” But Fredriksson, in a text mes- sage to Science, wrote, “We have been fired and kept in the dark.”
Several scientists suspect a link between their departure and a visit to Frey by poli- tician and former environmental activist Emmy Hafild—who supports the dam—and former environment minister Sonny Keraf. “It is our understanding that Hafild threat- ened PanEco on behalf of PT NSHE that if they did not fire Gabriella and Graham, it would be made very difficult for them to con- tinue to operate in Indonesia,” says Amanda Hurowitz, great ape program director at Mighty Earth. “That should not happen in a democracy,” Wich says. “It is a really black day for Indonesian conservation.”
By Jocelyn Kaiser
Cancer drug developers may be miss- ing their molecular targets—and never knowing it. Many recent drugs take aim at specific cell proteins that drive the growth of tumors. The strat- egy has had marked successes, such
as the leukemia drug Gleevec. But a study now finds that numerous candidate anti- cancer drugs still kill tumor cells after the genome editor CRISPR was used to elimi- nate their presumed targets. That suggests the drugs thwart cancer by interacting with different molecules than intended.
The study, published this week in Science Translational Medicine, points to problems with an older lab tool for silencing genes that has been used to identify leads for such drugs. The results also
cer agents. But to the group’s surprise, the MELK-deficient cells kept growing. And a drug thought to be aimed at MELK still stopped growth of the cells, suggesting its true target was not that protein.
That work spurred Sheltzer’s lab to collect examples of other drugs that target proteins found largely with RNAi. His group ulti- mately homed in on 10 drugs aimed at six proteins whose roles range from driving cell proliferation to controlling cancer gene ac- tivity. When the scientists used CRISPR to knock out the genes for those proteins in var- ious cancer cell lines, the cells kept growing, suggesting the original RNAi assay was mis- leading. Yet, when the team gave the relevant drug to cancer cells now missing the target protein, they still died—apparently through some other mechanism. “Many of the previ- ous results were replicable, butHafild denies that version of events. “I was just reminding them of the conse- quences if they keep opposing the dam,” she says. PanEco is allowed to do research and conservation in Indonesia, says Hafild, but not advocacy. “If my staff was conduct- ing a campaign that violates my agreement with the Indonesian government,” she adds, “of course I would fire them.” Frey says the meeting with Hafild, who she says is an old friend, was “very friendly.”
Scientists claim there have been other forms of pressure as well. Meijaard suspects PT NSHE was behind a press release head- lined “Electricity for Civilization,” from the
hint that the drugs in question, most of which are in clini- cal trials, and perhaps others could be optimized to work even better by pinning down their true mechanism.
“The work is very well done and it’s a great public service. I hope people talk about it. I don’t find any of it surprising, unfortunately,” says William Kaelin of the Dana-Farber Can- cer Institute in Boston, who has written about why promis- ing preclinical findings are of-
“Many of the previous results were replicable, but the interpretation was wrong.”
Jason Sheltzer, Cold Spring Harbor Laboratory
the interpretation was wrong,” Sheltzer says.
The researchers found a clue to the real mechanism for a drug, now in preclinical testing, that supposedly blocks a pro- tein called PBK, which aids cell division. By identifying cells that developed resistance to the drug, known as OTS964, and sequencing them for mutations that confer that trait, the lab showed the drug instead blocks the protein CDK11, which plays a different role in cell prolif-
Simanboru, an Indigenous community, that accused him and others of running a “black campaign” to influence the debate with false arguments. He also believes the com- pany instigated recent protests in Jakarta to demand the deportation of Fredriksson and Ian Singleton, another PanEco scientist.
Ismanto says those claims are baseless. “They accuse me of doing so many bad things,” he says. “They are just making things up.” He questions foreign scientists’ role in the debate, however: “Indonesia has been independent for decades and the orangutan is part of our natural riches,” he says. “We don’t need bule [white people] to protect them.” ■
Dyna Rochmyaningsih is a science journal- ist based in Deli Serdang, Indonesia.
ten not reproducible, or fail to lead to drugs. Leads for many recent targeted drugs emerged from experiments in which cancer cells were dosed with RNA strands that dis- rupt the natural RNAs that convey a gene’s protein-building instructions. After using this RNA interference (RNAi) method to zero in on genes essential to the growth of cancer cells, researchers screened libraries of molecules to find compounds that block
the genes’ proteins.
A few years ago, cancer biologist Jason Sheltzer of Cold Spring Harbor Laboratory in New York and colleagues used CRISPR’s gene-disabling skills, instead of RNAi, to pre- vent the manufacture of a well-established growth protein, called MELK, in cancer cells. Several companies at the time were developing MELK inhibitors as anti-can-
eration. Sheltzer calls this result “exciting” because inhibitors of other CDKs work well against breast cancer, and targeting this one could be a new option. (Science could not reach the drug’s manufacturer, OncoTherapy Science, for comment.)
Sheltzer doesn’t think his group’s results cast doubt on the targeted cancer drugs already on the market, as most have other compelling evidence they’re hitting the right protein. But for the 10 candidate drugs stud- ied by his lab, as well as others in develop- ment, it’s important to find out how they work so physicians can match patients to the best drug and fulfill the promise of precision medicine, Sheltzer says. Paul Workman of the Institute of Cancer Research in London agrees: “It clearly helps enormously if the true target is now found.” ■
SCIENCE sciencemag.org
13 SEPTEMBER 2019 • VOL 365 ISSUE 6458 1065
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CRISPR reveals some cancer drugs hit unexpected targets
Jocelyn Kaiser
Science 365 (6458), 1065.
DOI: 10.1126/science.365.6458.1065
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