Many drugs attack cancer by starving tumors of the fuels they need to grow and spread, whether it’s hormones, sugar, amino acids, fats or pro-growth signaling molecules.
The basic idea is that if a tumor cell depends on cupcakes, take away the cupcakes.
But what if the tumor cell is so cuckoo for cupcakes that it can’t help but eat every cupcake in reach, even if gobbling too many cupcakes would prove fatal?
Could feeding cancer so much of the thing it craves that it chokes on the surplus work as a therapy?
That’s a strategy Lucas Sullivan, PhD, a cancer metabolism researcher at Fred Hutch Cancer Center, proposes in a study published recently in Nature Metabolism.
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Sullivan and his colleagues explored the diet of fast-growing tumors with a genetic mutation affecting a molecule called NRF2 that is common in lung cancers but also appears in several other cancers.
That molecule normally turns genes on and off only in times of stress to protect cells from death, but the mutation in cancerous cells keeps NRF2 active all the time. This constant activation promotes tumor growth and protects cancer cells from chemotherapy and radiotherapy.
Many drugs are in the works that would decrease the activation of NRF2, but Sullivan’s research suggests a different way to do the trick.
Sullivan and co-authors Jennifer Brain, a graduate student, and Anna-Lena Vigil, a technician, both in his lab, tracked down what happens to a nutrient called cystine as it is broken down and used by healthy cells and cancerous cells with mutated NRF2.
They discovered that one of the products of that metabolism combines with sugar-containing molecules. Those sugar combos can accumulate to dangerous levels in tumor cells with overactive NRF2, causing cell death and decreasing the spread of the cancer.
The findings suggest a counterintuitive strategy (with apologies to Marie Antoinette, who probably never said “let them eat cake” when informed that the starving subjects of her husband’s kingdom in 18th century France had no bread.)
Rather than attempting to starve cancer cells of a nutrient that healthy cells also need, maybe tumor cells with overactive NRF2 can be force-fed so much of the stuff that they gobble cystine cupcakes until they die.
Sullivan has long tried to answer a simple question: What do fast-growing cancer cells eat and how do they use their food to make more cells?
“One of the things that has been known is that these NRF2-driven cancers just eat a ton of cystine,” Sullivan said.
Cystine is a precursor for cysteine, a building block for proteins, which are the molecules that do the cell’s work. It can be ingested or synthesized in the body.
NRF2 has many functions in both normal cells and tumor cells, including turning on a gene that helps transport cystine into the cells.
“Normal cells have this transporter,” Sullivan said. “Usually, it's at very low levels and it's only induced during stressful situations such as running out of amino acids. So, when cells sense that they're running out of amino acids, they say, oh no, let's bring in the transporter.”
Tumor cells with overactive NRF2 overproduce the transporter and cystine floods into the cells, providing way more of the nutrient than the cell would normally need.
“Every nutrient that we take in gets chemically modified as it goes through metabolism and becomes a new metabolite,” Sullivan said.
But when NRF2 opens the floodgates and keeps them open, the cells gobble way more cystine than they need for the known uses of cystine. Sullivan wanted to trace the destiny of all cystine-derived metabolites to find out what else the cell was doing with all the excess.
“It was one of my first projects when I got to Fred Hutch in 2018,” Sullivan said. “So it’s been a long haul.”
His lab in the Human Biology Division at Fred Hutch followed each cystine metabolite to its destination in cells with and without NRF2 activation.
They used a screening technique that applies a signal to the atoms of cystine, which persists within all its metabolites as the nutrient is broken down and used in the cell. Think of it like pouring green dye in the Chicago River on St. Patrick’s Day and then tracing everywhere that green water ends up in the city.
Their screen turned up expected uses for the cystine metabolites, such as the production of antioxidant protection, but the screen also revealed a few surprises.
Sullivan and his colleagues discovered several previously unknown cystine-derived metabolites that were mixed with sugars.
NRF2-activated tumor cells in both human and mouse samples had more sugar combos than non-NRF2-activated cells, suggesting that they play a helpful role in normal cellular physiology that changes in cancerous cells.
The sugar combos come in two forms: reversible and irreversible. The reversible ones can be managed, but the irreversible sugar combos pile up when there’s too much cysteine in the system, causing slower growth and cell death.
“We think it's the cysteine itself that is a problem, but we don't actually know why,” Sullivan said. “It could be that cysteine is reactive and it's reacting with something else that we didn't detect. Maybe it's reacting with DNA or proteins or gumming up the works in some other way.”
But if excess cystine consumption caused by the NRF2 mutation carries such risks, why do so many cancers have it?
On balance, the cancerous cells can manage the cystine overload well enough so that the tumor-promoting benefits of NRF2 outweigh the costs, making the trade-off worth it.
Many therapies aim to disrupt the NRF2 signaling pathway and take away those benefits, but Sullivan and his team had a different idea.
What if they could tip the scales so the trade-off isn’t worth it?
“We could lean on that and make that cost more severe by giving them more cystine,” Sullivan said.
A dietary supplement could boost cystine levels so high that the tumor cells could no longer compensate. The excess would bury the tumor cells in irresistible cupcakes.
But it wouldn’t harm healthy cells because those cells normally moderate their cystine intake, turning down the cupcakes when they’ve had enough.
“Normal cells don't have this problem,” Sullivan said. “These cancer cells do.”
Researchers call precision therapies that exploit such differences between normal cells and tumor cells synthetic lethality.
“That’s the real utility of this down the line,” Sullivan said.
The next step is to figure out in preclinical models how much dietary cystine would be needed to kill tumor cells and leverage that vulnerability to develop a new therapy for NRF2-driven cancers.
This work was supported by the Proteomics and Metabolomics Shared Resource (funded by an NCI Cancer Center Support Grant for the Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium), the National Institute of General Medical Sciences, the National Science Foundation and an anonymous donor.
John Higgins, a staff writer at Fred Hutch Cancer Center, was an education reporter at The Seattle Times and the Akron Beacon Journal. He was a Knight Science Journalism Fellow at MIT, where he studied the emerging science of teaching. Reach him at jhiggin2@fredhutch.org or @jhigginswriter.bsky.social.
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