Researchers at Sanford Burnham Prebys have shown for the first time that inhibiting a key metabolic enzyme selectively kills melanoma cells and stops tumor growth. The team, led by Ze’ev Ronai, PhD, professor and director of the NCI-designated Cancer Center at Sanford Burnham Prebys, found that melanoma is addicted to the enzyme glutaryl-CoA dehydrogenase (GCDH), and its inhibition leads to changes in a protein called NRF2, which then acquires the ability to suppress melanoma. The studies demonstrated that genetic inhibition of GCDH expression effectively suppressed melanoma growth in culture and in mice. The team hopes that their findings could lead to a new class of drugs to selectively treat melanoma, the most severe form of skin cancer.
“We found that melanoma is addicted to an enzyme called GCDH,” said Ronai. “If we inhibit the enzyme, it leads to changes in a key protein, called NRF2, which acquires its ability to suppress cancer. Now, our goal is to find a drug, or drugs, that limit GCDH activity, potentially new therapeutics for melanoma.”
Ronai and colleagues published their results in Nature Cell Biology, in a paper titled, “NRF2 mediates melanoma addiction to GCDH by modulating apoptotic signaling,” in which they concluded, “Our in vivo data indicate that genetic GCDH inhibition attenuates melanoma growth, suggesting that GCDH is required for tumor cell growth, and may thus serve as a therapeutic target in this tumor.”
Metabolic pathways that supply energy to normal cells are often rewired in cancer to ensure that the rapidly proliferating cancer cells have sufficient energy, the authors explained. And because tumors grow quickly and require lots of nutrition, researchers have been investigating potential ways of starving cancer cells. “Addiction to a particular metabolic pathway is common to tumor cells promoting attempts to reverse tumor cell addiction by targeting a specific pathway or restricting the availability of a particular amino acid,” the team noted. But as promising as this approach might seem, the results have not been as hoped. Denied one food source, cancers invariably find others. “ … strategies to limit glutamine, asparagine, serine/glycine, or methionine had limited success, often due to compensatory signaling,” the investigators further acknowledged.
GCDH is a mitochondrial protein that plays a significant role in metabolizing lysine and tryptophan, amino acids that are essential for human health. When the Ronai lab began interrogating how melanoma cells generate energy from lysine, they found that GCDH was mission critical.
“Melanoma cells ‘eat’ lysine and tryptophan to produce energy,” said Sachin Verma, PhD, a postdoctoral researcher in the Ronai lab and first author of the study. “However, harnessing energy from this pathway requires cancer cells to quench toxic waste produced during this process. It’s a six-step process, and we thought the cells would need all six enzymes. But it turns out only one of these enzymes is crucial, GCDH. Melanoma cells cannot survive without the GCDH portion of the pathway.”
Further experiments showed that inhibiting GCDH in an animal model gave NRF2—“a master transcriptional regulator of the stress response implicated in cellular oxidative, nutrient, and metabolic stress response”—cancer-suppressing properties. “In vivo inhibition of GCDH expression effectively blocked tumor growth,” the scientists wrote. Collectively, they noted, their findings “… establish the importance of GCDH for melanoma growth in vivo.”
Prior studies have found that NRF2 can exhibit either oncogenic or tumor suppressor activities, in different cancer models, but how hasn’t been understood. Ronai added, “We’ve known for a long time that NRF2 can be both a driver and a suppressor of cancer. We just didn’t know how we convert NRF2 from a driver to suppressor function. Our current study identifies the answer.”
The researchers also found that inhibiting GCDH was rather selective for melanoma tumors. Similar efforts in lung, breast, and other cancers had no impact, possibly because those cancers may be addicted to other enzymes. And interestingly, they noted, “… reduced GCDH expression correlated with improved survival of patients with melanoma.”
Summarizing their results, the team said, “Our studies revealed that GCDH controls NRF2 stability by regulating NRF2 glutarylation and tumor suppressor function.” Loss of GCDH then induces NRF2 glutarylation and increases its stability. This causes transcriptional upregulation of certain pathways, and ultimately leads to melanoma cell death. “Correspondingly, genetic inhibition of GCDH expression effectively suppressed melanoma growth in culture and in mice … Inhibiting the GCDH pathway could thus represent a therapeutic approach to treat melanoma.”
From a therapeutic standpoint, the study reveals several possible options. Though animal models without GCDH were basically normal, they could not tolerate a high-protein diet. This is significant because some melanoma patients’ tumors are also low in GCDH. Given the enzyme’s role in processing proteins, the authors believe GCDH-poor tumors may also be vulnerable to high-protein foods, setting up a potential dietary treatment. In addition, reducing GCDH levels in tumors may be complemented with select protein diets.
GCDH inhibition shows significant therapeutic promise. Because normal cells without GCDH are mostly unaffected, GCDH inhibitors would be quite specific to melanoma cells. The Ronai lab is now working with scientists at the Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys to identify small molecule GCDH inhibitors that could be the starting point for future melanoma treatments.
“In the study, we used genetic approaches to inhibit GCDH, which provide the proof of concept to search for small molecules inhibitors,” said Verma. “Indeed, we are actively searching for potential drugs that could inhibit GCDH, which would be candidates for novel melanoma therapies.”