Researchers have shown for the first time that inhibiting a key metabolic enzyme selectively kills melanoma cells and stops tumour growth – which could lead to a new class of drugs to selectively treat melanoma, the most severe form of skin cancer.
The study at Sanford Burnham Prebyshave was led by Ze’ev Ronai, PhD and published in Nature Cell Biology.
“We found that melanoma is addicted to an enzyme called GCDH,” said Ronai, professor and director of the NCI-designated Cancer Centre at Sanford Burnham Prebys. “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.”
Because tumours grow rapidly and require lots of nutrition, researchers have been investigating ways to starve cancer cells. As promising as this approach may be, the results have been less than stellar. Denied one food source, cancers invariably find others.
GCDH, which stands for Glutaryl-CoA Dehydrogenase, plays a significant role in metabolisng 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 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 exploration showed that inhibiting GCDH in an animal model gave NRF2 cancer-suppressing properties. “We’ve known for a long time that NRF2 can be both a driver and a suppressor of cancer,” said Ronai. “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 tumours. Similar efforts in lung, breast and other cancers had no impact, probably because those cancers may be addicted to other enzymes.
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’ tumours are also low in GCDH. Given the enzyme’s role in processing proteins, the authors believe GCDH-poor tumours may also be vulnerable to high-protein foods, setting up a potential dietary treatment. In addition, reducing GCDH levels in tumours 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 Centre 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.”
Sanford Burnham Prebyshave in La Jolla, California, is a non-profit medical research institute focusing on basic and translational research, with major research programmes in cancer, neurodegeneration, diabetes, and infectious, inflammatory and childhood diseases. The institute also specialises in stem cell research and drug discovery technologies.
Study details
NRF2 mediates melanoma addiction to GCDH by modulating apoptotic signalling.
Sachin Verma, David Crawford, Ali Khateb, Yongmei Feng, Eduard Sergienko, Gaurav Pathria, Chen-Ting Ma, Steven Olson, David Scott, Rabi Murad, Eytan Ruppin, Michael Jackson, Ze’ev A. Ronai.
Published in Nature Cell Biology on 1 September 2022.
Abstract
Tumour dependency on specific metabolic signals has been demonstrated and often guided numerous therapeutic approaches. We identify melanoma addiction to the mitochondrial protein glutaryl-CoA dehydrogenase (GCDH), which functions in lysine metabolism and controls protein glutarylation. GCDH knockdown induced cell death programmes in melanoma cells, an activity blocked by inhibition of the upstream lysine catabolism enzyme DHTKD1. The transcription factor NRF2 mediates GCDH-dependent melanoma cell death programmes. Mechanistically, GCDH knockdown induces NRF2 glutarylation, increasing its stability and DNA binding activity, with a concomitant transcriptional upregulation of ATF4, ATF3, DDIT3 and CHAC1, resulting in cell death. In vivo, inducible inactivation of GCDH effectively inhibited melanoma tumour growth. Correspondingly, reduced GCDH expression correlated with improved survival of patients with melanoma. These findings identify melanoma cell addiction to GCDH, limiting apoptotic signalling by controlling NRF2 glutarylation. Inhibiting the GCDH pathway could thus represent a therapeutic approach to treat melanoma.
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