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.
Alan Ashworth, President of the Helen Diller Family Comprehensive Cancer Center at UCSF and co-director of the CRISPR Cures for Cancer initiative.
“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.
“People generally, and especially in the gene editing field, want to fix genes or knock out genes,” says Zeng. “But what I wanted to do here is completely different. I wanted to destroy abnormal cells, precisely and safely.”
This approach takes CRISPR back to its roots; in nature CRISPR systems are destroyers not fixers. They defend microbes against infections by cutting the genetic material of invading viruses to prevent damage and replication. Instead of reactivating a broken p53 protein, the research team reasoned that they could harness CRISPR’s natural ability to find cells with specific mutations and use its cutting ability to selectively destroy those cells.
Jingkun Zeng, postdoctoral researcher in the Doudna Lab at the IGI and Gladstone Institutes
The research team engineered a CRISPR system called CRISPR-Cas12a2 to look for the specific RNA transcript produced only by cells with the mutated cancer gene. In bacteria, this CRISPR acts as a suicide pill, intentionally killing a cell that has been infected by a virus to prevent its spread. In the newly engineered version, once the system detects a cancer signature within a cell, the Cas12a2 enzyme activates and initiates “chromatin shredding,” slicing up all the genetic material inside that specific cell. This widespread genetic demolition triggers cell death, destroying mutated cells while leaving healthy cells completely untouched.