Mutant’s partner in crime could be target for future cancer therapy

When you can’t take down the kingpin, go after his accomplices. This strategy may work for cancer as well, according to scientists at Fred Hutch Cancer Center and Memorial Sloan Kettering Cancer Center. In work published today in the journal Molecular Cell, the team described a novel factor that abets a cancer-promoting mutant in skewing a critical biological process called RNA splicing. They found that deleting the new factor — instead of the mutant — shifts abnormal RNA splicing patterns back toward normal.

“It’s not common to find a new splicing factor, let alone one that does something important,” said co-senior author and Fred Hutch RNA processing expert Robert Bradley, PhD, who holds the McIlwain Family Endowed Chair in Data Science. “It’s pretty remarkable.”

Splicing factor mutations are common in certain blood cancers and disorders of blood cell development. In preclinical models, Bradley and co-senior author, MSK oncologist Omar Abdel-Wahab, MD, showed that when they removed the new splicing factor, called GPATCH8, from cells with a cancer-associated mutation in a different splicing factor, they could restore normal blood-cell development.

“GPATCH8 is not required for the survival of normal cells,” said Abdel-Wahab, who treats leukemia patients while studying how alterations in DNA drive blood cancers. But splicing factor-mutant cells need GPATCH8 to survive, “which makes it a very attractive potential therapeutic target.”

Diseases that could benefit from strategies that target the molecules that collude with mutant splicing factors include blood cancers like chronic leukocytic leukemia (CLL) and blood disorders like myelodysplastic syndrome (MDS), as well as melanomas that arise outside the skin, such as uveal melanoma.

“These are diseases where there's still a really great need for improved therapies,” Abdel-Wahab said. “It’s a novel idea: Targeting not the splicing factor — which is essential — but the factor that facilitates its aberrant splicing, but not normal splicing patterns.”

RNA processing and cancer

Our genes encode our proteins, but “messenger” RNA is the essential molecule that allows our cells to turn genetic information into tangible strings of amino acids. But hot-off-the-DNA RNA transcripts aren’t ready for protein production — they’re first drafts that need an editor.

“Surprisingly, our genes are interspersed with non-coding genetic material, called introns,” Abdel-Wahab said.

Introns, which intermingle with protein-coding gene sections (called exons), need to get snipped out to produce an RNA molecule that our protein-producing factors can use. Splicing factors help regulate the process of snipping out introns and splicing exons back together.

“RNA is like an email,” Bradley said. “Edits can make a big difference in the message you’re sending.”

Different mixtures of protein-coding segments generate RNAs that are the blueprints for different forms of proteins with different activities. Cancer-promoting mutations in splicing factors don’t block their activity. Instead, they cause splicing patterns to shift; some protein forms get produced at much higher levels than normal, some at much lower levels.

Mutant splicing factors can also go rogue and splice at entirely new sites, generating new proteins not found in normal cells.

Bradley and Abdel-Wahab study a splicing factor called SF3B1. In 2019 they established how mutant SF3B1 drives cancer. But SF3B1 (mutated or not) is essential to cellular survival, making it (so far) undruggable. And there’s a lot yet to understand about how mutations in SF3B1 change how it works. To better understand how mutant SF3B1 wreaks splicing havoc, the team widened their view.

“We wanted to look for genes that are required by mutant SF3B1 to perform its pathogenic splicing activity,” Abdel-Wahab said.