Although aberrant MYC activity confers protumorigenic effects on cancer cells, it also adds stress by increasing the amount of pre-mRNA substrates for the spliceosome to process. New research indicates that MYC-driven cancers depend on an intact, functional spliceosome for survival; targeting this multiprotein complex could therefore be an indirect therapeutic strategy against a highly drug-resistant oncogene.

Despite efforts to quell hyperactive MYC in cancer, this oncogene remains remarkably resistant to therapeutic targeting. However, a new study suggests that MYC-driven cancers do have an Achilles' heel: To survive, the cells require a fully functional spliceosome—the multiprotein complex that prepares immature mRNA for translation by joining together coding sequences called exons after first removing introns, or intervening stretches of noncoding DNA (Nature 2015;525:384–8).

“MYC is aberrantly activated in a third of cancers, and has the unusual function of ramping up transcription across much of the cancer cell genome,” says senior author Thomas Westbrook, PhD, an associate professor at Baylor College of Medicine in Houston, TX. “This stimulation of widespread RNA synthesis may be protumorigenic, but it also places a heavier burden on the spliceosome. Basically, oncogenic MYC comes at a cost to cancer cells.”

Westbrook and his team began uncovering the spliceosome's importance in MYC-driven cancers when a genetic screen revealed synthetic lethality between MYC and a gene called BUD31. They went on to confirm that in the absence of BUD31, human mammary epithelial cells with hyperactive MYC ceased proliferating and underwent apoptosis. Rather than zeroing in on BUD31 as a key culprit and potential therapeutic target, the researchers decided to find out more about this little-known protein.

“We cataloged all the proteins associated with BUD31, and what we got, essentially, was the spliceosome,” explains Tiffany Hsu, an MD/PhD candidate at Baylor and the study's lead author. When the researchers systematically inactivated or reduced the function of not only BUD31, but also other core components of the spliceosome, “we saw the same effect each time—MYC-hyperactive cells simply couldn't tolerate such perturbations, however small,” Hsu adds. These cells suffered widespread defects in mRNA maturation that led to the deregulation of essential processes like DNA replication, mitosis, and metabolism.

“So, the key here isn't BUD31,” Westbrook emphasizes, “but rather that the survival of MYC-driven cancer cells depends on the spliceosome operating at maximum efficiency. We showed that normal cells, on the other hand, are fine with modest reductions in spliceosome function.”

The researchers also showed that SD6, a new small-molecule inhibitor targeting a core spliceosome protein called SF3B1, was effective in a mouse model of triple-negative breast cancer, an aggressive subtype largely fueled by aberrant MYC activity. SD6 impeded the growth of both primary tumors and lung metastases in the mice, without obvious toxicities. Targeting the spliceosome could therefore be an indirect way to prevail over this recalcitrant oncogene, and SD6 is just the tip of the iceberg, Westbrook points out. With more than 100 core spliceosome proteins in all, “there's lots of room to maneuver in this therapeutic space.”

“We're far from understanding all the ways hyperactive MYC confers vulnerabilities even while spurring cancer cell growth,” he adds. “The more we learn, the better we can selectively target these cancers, by finding ways to exacerbate their oncogene-induced collateral stress.”

For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.

©2015 American Association for Cancer Research.
2015