Scientists at the Theodor Boveri Institute at the University of Würzburg in Germany have potentially found a way to indirectly target the MYC oncogene—an elusive cancer therapy target. Martin Eilers and colleagues discovered that cancer cells with upregulated levels of MYC are dependent on AMPK-related kinase 5 (ARK5) to stay alive. ARK5, it turns out, is necessary for these cells to maintain metabolic homeostasis. The study, published last month in Nature, shows that inhibition of ARK5 causes these MYC-dependent cells to die, partly due to depriving them of cellular ATP, leading to apoptosis.
The research validates the connection between MYC and ARK5 expression seen in several primary solid tumor samples, including liver and pancreatic carcinomas.
ARK5 may be a potential drug target for tumors that overexpress MYC, according to the authors. This would be a way to get around the problem of targeting MYC itself. In general, the authors highlight that targeting the “oncogene-altered energy metabolism” pathways in tumor cells may be a new way to isolate cancer therapy targets.
The MYC gene was discovered in the 1970s in Burkitt lymphoma patients. MYC encodes a transcription factor that is important for regulating many pathways involved in cell growth, cell cycle progression, and apoptosis. It is an oncogene that is found deregulated in many cancer types. MYC does not have good target-binding sites and is far away from the cell membrane, two reasons that help explain why no good drug candidates have been able to target the protein.
“MYC is such an elusive target since it is a transcription factor with large protein-protein interaction surfaces,” explains Eilers.
The Study and Results
The researchers identified ARK5 and a related kinase, AMPK in a short-interfering RNA screen using a human cancer cell line overexpressing MYC. The purpose of the screen was to identify factors that facilitate the survival of MYC overexpressing cancer cells. When ARK5 was depleted, the MYC-expressing cells showed signs of apoptosis. The study found that the levels of MYC protein necessary for dependence on ARK5 are much higher than the MYC levels that are required to induce proliferation. Induced expression of apoptosis-inhibiting factor did not alleviate the dependence of the cells on ARK5.
The experiments in the published paper show that ARK5 helps cancer cells survive in a metabolically stressful environment induced by MYC hyperactivity.
In an MYC-overexpressing liver cancer mouse model, the researchers show that ARK5 is important. "ARK5 is necessary to maintain sufficient respiratory capacity in MYC-transformed cells,” state the authors. Depletion of ARK5 caused cells to undergo the cell cycle in a much slower manner, showing that ARK5 facilitates cell growth. This demonstrates the synthetic lethality of deregulated MYC expression and inhibition of ARK5.
The study also showed that the synthetic lethality of high MYC expression and loss of ARK5 could be rescued by addition of rapamycin. Rapamycin is a drug that inhibits the mammalian target of rapamycin (mTOR) pathway that is involved in cell survival and proliferation. This shows, explained Eilers, that deregulation of mTOR is the “key mode” of cell death as mTOR inhibitors can protect cell viability in MYC-overexpressing cells that are depleted of ARK5.
To test the potential therapeutic efficacy of ARK5 depletion, the study researchers transplanted mouse liver cancer cells that express MYC—depletion of ARK5 caused cell death, and rapamycin restored ATP levels and sustained the ARK5-depleted culture. The transplanted cells resulted in 8 of 8 carcinomas in mice.
“We propose that negative regulators of the mTOR pathway, like ARK5, may be good targets for therapy of MYC-expressing tumors,” says Eilers.
“The key question, in my view, is whether the metabolic crisis that we observe in tissue culture when we deplete ARK5 in MYC-expressing cells, is also seen in vivo in human tumor cells,” says Eilers. The evidence for the metabolic imbalance created by removing ARK5 has so far only been shown in engineered mouse cells in vivo.
Eilers says that there are currently no available inhibitors of ARK5 but that he believes it is a good idea to develop them to test them in MYC-expressing tumors. He adds that recent work from the laboratory of James Bradner, MD at the Dana-Farber Cancer Institute in Boston, on compounds that inhibit a protein called BRD4 is “an exciting approach.” BRD4 functions to activate MYC.
“Targeting MYC, after all these years, is becoming a rational approach for developing tumor therapies,” says Eilers.