GoKawiilInnovative chromatin shredding technique shown to selectively destroy cancer cells carrying a mutation found in nearly half of all cancer cases
The job of a tumor suppressor protein is right in the name: stopping us from getting cancer at the cellular level. But when they’re not working properly, the cell is left with limited defenses.
In a new paper published today in the journal Nature titled “Targeting Cancer-Specific Mutations with RNA-Triggered Chromatin Shredding,“ researchers at the Innovative Genomics Institute (IGI) at UC Berkeley, UC San Francisco, and Gladstone Institutes, along with collaborators at University of Utah and Utah State University, report that a creative new CRISPR-based approach can selectively destroy cells carrying a mutation in a tumor suppressor found in nearly half of all cancers and up to 70–90% of cases of some of the most difficult-to-treat cancers, including ovarian, pancreatic, and non-small cell lung cancer.
“Not only can this approach target the ‘undruggable’ cancers that we know, we can also easily and quickly adapt this to new mutations,” says IGI Founder Jennifer Doudna, a co-author on the paper. “This is an exciting development for cancer therapies, and potentially for other applications as well.”
A common mutation behind many cancers
First author Jingkun Zeng, a postdoctoral researcher in Doudna’s lab, did his Ph.D. research at the Francis Crick Institute on cancer evolution and was looking to find new ways to target the so-called “undruggable” cancer mutations and thought tumor suppressors might hold the key.
“If you look at all the cancer drugs right now, they’re mostly inhibitors. They suppress an overactive cancer gene,” says Zeng. “But for tumor suppressors, it’s the opposite. When they develop a mutation, they lose their function. They can no longer suppress tumor formation.”
The role of a specific protein called p53 as a tumor suppressor has been known since the late 1980s. Mutations in this gene help cancers grow uninhibited and are common across many cancer types. Because of this, and because it is often an early mutation that drives later mutations in the cancer-causing cascade, researchers have long considered it one of the premium targets for cancer therapy. Despite the promise, not a single p53-targeting drug has made it to the market. Not only do tumor suppressor proteins lack “druggable pockets,” the areas on the molecule where small molecule drugs can fit like a key in a lock, it’s not clear how drugging mutated p53 protein could help it do its job.
Going back to CRISPR basics
Zeng, inspired by reading a paper from the Doudna Lab on using CRISPR to shred repetitive sequences in brain tumors, thought there might be an alternative to reactivating broken tumor suppressors: finding cells with cancer-specific mutations and eliminating them entirely.
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