A drug with promising preclinical results against treatment-resistant cancer might also be effective against COVID-19.
In the results of a study published Nov. 14 in Nature Communications, scientists from the University of California (USC) Keck School of Medicine and the Cleveland Clinic Florida Research and Innovation Center described how they discovered that a drug that inhibits glucose-regulated protein 78, or GRP78, suppresses SARS-CoV-2 replication in the lungs of mice. In an earlier study, the USC team showed the same drug could lower the expression of KRAS, a cancer-promoting protein, in mouse models of a deadly subtype of cancer.
“It turns out that cancer and COVID act on cells in similar ways,” Amy Lee, Ph.D., co-corresponding author and professor of biochemistry and molecular medicine at USC, told Fierce Biotech Research.
When a cell is under stress—such as exposure to toxins, extreme temperatures, physical damage or viral infection—it needs more GRP78 to properly function. The transformation from a healthy cell to a cancerous one is a form of cell stress, too. Cancer cells take advantage of enhanced GRP78 expression to grow and survive.
Lee has been studying the protein’s role in cancer for most of her career. In fact, she was the first person to clone human GRP78. In early 2020, her lab was busy researching the link between the protein and the development of KRAS-mutated cancer cells, as well as other projects on GRP78's function in cancer.
“Then COVID came around,” Lee recalled. When lockdown went into effect, any labs that weren’t actively working on COVID-19-related projects had to shut down—including Lee’s. But a review of earlier literature turned up something compelling. Research on other coronaviruses, including the one behind the Middle East respiratory syndrome outbreak, suggested that they used GRP78 to enter cells.
“There were rumblings that GRP78 is quite important to a lot of viruses,” Lee said. She directed her lab to work on figuring out whether SARS-CoV-2 might be one of them.
Their initial results, published in 2021, showed that the virus did indeed hijack GRP78 to infiltrate cells and reproduce. But it wasn’t clear that GRP78 was truly essential to viral replication.
To find out, the research team infected human lung cells with SARS-CoV-2 and watched how GRP78 levels changed over time. After seeing that the protein levels increased as infection progressed, the scientists took the inverse approach: In a different set of cells, they “knocked down” the protein—or prevented it from being created—then infected them with the virus. Cells without GRP78 had less SARS-CoV-2 spike protein and lower infectious virus production, indicating that the protein was essential for its replication.
With the protein’s necessity confirmed, it was time to see if targeting GRP78 could treat COVID-19. First, the scientists infected cells with SARS-CoV-2, then added HA15—a small-molecule GRP78 inhibitor that keeps it from regulating protein assembly. The drug reduced both the size and number of SARS-CoV-2 plaques that formed, and there was a greater reduction as the dose increased.
Finally, the scientists turned to live models. They injected mice that were infected with SARS-CoV-2 for three days, beginning on the day of infection. At the end of the period, the viral load in their lungs was tenfold lower than in controls.
“We hypothesize that anti-GR78 agents in combination with anti-SARS-CoV-2 therapeutics could further suppress SARS-CoV-2 infection since GRP78 inhibition can deprive the virus of an essential chaperone for their entry and viral protein production,” the scientists wrote in their paper.
Lee’s other work with HA15 has suggested that it holds promise for treating KRAS-mutated cancers, too. Once thought to be an “undruggable” disease, it was only last year that the FDA approved the first drug to treat KRAS-mutated cancer, Amgen’s Lumakras. And the FDA is expected to weigh in on Mirati Therapeutics' adagrasib by Dec. 14, while several candidates are in various stages of clinical trials.
In a paper published in September, Lee’s lab shared results that suggested that GRP78 inhibition with HA15 might be another worthwhile therapeutic strategy. In both cell lines and mouse models, the team showed that the drug (along with another GRP78 blocker, YUM70) could reduce tumors and the levels of the KRAS protein.
While the mechanism behind the way GRP78 contributes to viral replication is straightforward, exactly how it regulates KRAS is much less so, Lee said. “If I knew that, I’d have another Nature paper,” she added.
Lee’s team is pursuing those answers now, as well as elucidating GRP78’s many different roles in different parts of cancer cells. As for COVID-19, they will need to find out whether the lower burden of lung disease they saw in mice treated with HA15 translates to higher survival rates. They already have some signs that will be the case—infected mice who were given the drug didn’t lose weight, for instance, a hint that it was protecting them from severe disease—but they’ll need to do more research to be sure. They also plan to test other GRP78-blocking drugs besides HA15.
“Seeing that the weight loss is averted suggests there is a survival benefit, but we have to firm up the data,” Lee said. “It’s promising.”
The scientists also plan to study how GRP78 might play a role in long COVID, a syndrome characterized by severe fatigue, cardiac issues, breathing problems and more that has been shown to follow SARS-CoV-2 infection in some patients.“That’s going to be the next important area of research,” Lee said.