Bacterial protease takes on ‘undruggable’ oncoprotein

By Anette Breindl
February 25, 2021

Scientists, despite their best efforts, have not been able to identify a way to inhibit the oncoprotein Myc. Uropathogenic Escherichia coli (UPEC), though, has apparently figured it out.

In the Feb. 11, 2021, online issue of Nature Biotechnology, researchers reported that an UPEC-produced protease depleted cellular Myc and improved survival in mouse models of bladder and colon cancer. The findings, Catharina Svanborg told BioWorld, are “in part a serendipitous observation that we were prepared for by having an interest in immunology and cancer.”

Svanborg is a professor in the division of microbiology, immunology and glycobiology at Lund University.

Myc is a transcription factor that regulates multiple cellular growth factors. Its overexpression is a driver event in many solid tumors, making it one of cancer’s Most Wanted. Its structure, though – or rather, its lack thereof – has so far stymied any attempts at small-molecule inhibition, as Myc does not have the sort of pockets that are often the target of successful small-molecule drug development campaigns. The work now published in Nature Biotechnology began with a study on infants with kidney infections. When comparing gene expression profiles in samples taken during acute infections and after the end of anti- biotic treatment, the researchers found that Myc expression was markedly lower during acute infection.

Follow-up experiments in vitro showed that three quarters of UPEC strains inhibited Myc production, and that Myc levels fell within hours of infection.

“The next step was to do a lot of genetic mutation analysis with our colleagues,” Svanborg said, “to see where this ability to affect Myc is located.” The team went on to identify a bacterial protease, the Lon protease, as the specific causal protein. UPEC strains produced and secreted Lon protease, which were taken up by kidney cells. There, Lon targeted Myc both directly and indirectly. The protease was able to cut Myc, but also increased its phosphorylation by ca- sein kinase 1α, which led to increased degradation by the cellular proteasome.

Svanborg and her team next tested whether the Lon protease could inhibit Myc in animal models of colon and bladder cancer. In a bladder cancer model, while animals treated with Lon protease administered directly into the bladder did develop tumors, they were smaller than those developed by control animals. In a model of APC-driven colon cancer, Lon administration reduced the number of precancerous polyps. In both models, Svanborg said, “if we take the bacterial protein as a drug and treat animals with tumors of the intestine or the bladder… the tissues are returning to almost a healthy phenotype.” In healthy animals, “we see a very different response, [suggesting that] the exaggerated Myc phenotype is targeted, and not the healthy tissue – which would be fantastic.” Svanborg and her team plan to continue preclinical development of the protease, and are looking for a bio- pharma collaborator to do so.

The researchers also want to test the approach in other tumor types, as Myc is overexpressed in many solid tumors.
“The reason that we used these mucosal models is because we could apply the compound locally and follow the local effect, and it’s quite dramatic,” Svanborg said. But “once the compound is known, there’s no reason not to apply it to other tumors.” Beyond UPEC and Lon, searching for bacterial proteins that affect oncoproteins might also be a more gen- eral strategy. Bacteria, which live in polymicrobial communities whose members are often in competition with each other, produce many antibacterial compounds. The new results show that the interplay between bacteria and their host cells may similarly yield useful starting points for drug development. “The conceptual novelty here is wonderful,” Svanborg said, “because you could speculate that bacteria pop- ulate the intestine….inadvertently protect against tumor development.”