Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Scientists from the Cancer Dependency Map (DepMap) at the Broad Institute of MIT and Harvard and Columbia University have discovered that about 5 percent of adult cancers rely heavily on a gene called PELO to survive and that disabling the gene kills those cancer cells. These cancers have mutations in one of two genes, FOCAD or TCC37.

The finding, described today in Nature, is a new synthetic lethality — a pair of genetic changes that together kill cancer cells. The researchers say that PELO is a promising target, and that genetic testing could identify cancer patients with FOCAD or TCC37 mutations who would benefit from new PELO-targeting drugs.

“These cancers are a huge unmet medical need, because we don’t have effective drugs for them,” said Francisca Vazquez, co-senior author on the study along with postdoctoral researcher Edmond Chan, now an assistant professor at Columbia University. Vazquez is also director of DepMap, which systematically probes cancer cell lines for genetic vulnerabilities. 

“Targeting synthetic lethalities is a good way to expand the repertoire of tumors we’re able to treat,” Vazquez said. “This new synthetic lethality we found shows how powerful the DepMap datasets can be.”

Patricia Borck, a DepMap research scientist in Broad’s Cancer Program, is first author on the study.

Lethal pairings

The team began by looking for ways to target a common set of cancers in which both copies of chromosome 9 have a deletion in a region called 9p21.3. These mutations occur in a range of deadly cancers including those of the brain, bladder, pancreas, esophagus, and lungs.

The scientists analyzed datasets from DepMap’s genome-wide CRISPR knockout screens in more than 1,200 cell lines. They noticed that cell lines with very few copies of the 9p21.3 sequence died when PELO was disabled. They then found that deletions within the FOCAD gene specifically caused the cells’ dependency on PELO.

But the cells with 9p21.3 deletions were not the only ones with a PELO dependency. Another group of cells with high microsatellite instability — mutations in short repeated DNA sequences, specifically in the TTC37 gene — had the same sensitivity. That meant there are potentially two groups of patients who might benefit from drugs targeting PELO: those with deletions in FOCAD and others with deletions in TTC37, which are found in colorectal and endometrial tumors.

Superkiller complexes

Next, Vazquez, Chan, and their team wanted to understand why mutations in FOCAD and TTC37 left cells vulnerable to PELO loss. PELO encodes a protein responsible for restarting ribosomes when they stall on defective mRNA sequences during protein production. The FOCAD and TTC37 proteins are part of — and help stabilize — an assembly called the “superkiller complex,” which extracts RNA from stalled ribosomes.

In the lab, the researchers found that cells with lower levels of the FOCAD and TTC37 proteins were more dependent on PELO. This suggests that cells compensate for mutations in the FOCAD and TTC37 proteins by using PELO to restart stalled ribosomes. But without PELO, cells aren’t able to restart protein production and eventually die.

Next, the team wants to better understand the role both PELO and the superkiller complex play in human cells. They also aim to pinpoint the degree to which a new drug would need to inhibit PELO to be therapeutically effective.

Vazquez thinks it’s possible that there are other genes that may have synthetic lethality relationships with PELO, which could further expand the range of patients who might benefit from a potential drug.