MYCN-Amplified Neuroblastomas Are Glutamine Dependent

Overexpression or amplification of MYC oncogenes rewires cellular metabolism and confers sensitivity to glutamine deprivation in vitro, but the mechanisms that underlie MYC-induced glutamine dependence are not well understood and the clinical relevance of these observations remains uncertain. Because MYCN amplification occurs in approximately 25% of neuroblastomas, this cancer represents an attractive model for studying the role of MYC in cell death caused by glutamine loss. Qing and colleagues showed that MYCN-amplified neuroblastoma cells were more sensitive to glutamine starvation than were nonamplified cells and that MYCN knockdown prevented cell death upon glutamine depletion. Moreover, expression analysis of 80 primary neuroblastomas showed that multiple genes involved in glutamine metabolism were significantly upregulated in MYCN-amplified tumors compared with nonamplified tumors, suggesting that glutamine dependence may also be a feature of some human tumors. Glutamine starvation–induced cell death in MYCN-amplified neuroblastoma cells was dependent on activating transcription factor 4 (ATF4), which directly increased expression of the proapoptotic genes PUMA, NOXA, and TRB3 in response to glutamine deprivation. Consistent with these findings, pharmacologic inhibition of glutamine metabolism or activation of ATF4 elicited a phenotype in MYCN-amplified cells similar to that caused by glutamine starvation and blocked tumor growth in vivo. Intriguingly, 2 drugs that are well tolerated in humans, epigallocatechin gallate (EGCG), a glutamate dehydrogenase inhibitor, and fenretinide (FRT), a chemotherapeutic agent that activates ATF4, had selective activity against MYCN-amplified neuroblastoma cells whether the drugs were used alone or in combination. Furthermore, these drugs also induced PUMA/NOXA/TRB3-dependent cell death and tumor inhibition in MYC-overexpressing Burkitt lymphoma cells, indicating that glutamine dependence may be a general feature of MYC-overexpressing tumors. Therapeutic exploitation of MYC-dependent cell death pathways and metabolic alterations may therefore be effective in human tumors that overexpress MYC oncogenes.

Qing G, Li B, Vu A, Skuli N, Walton ZE, Liu X, et al. ATF regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation. Cancer Cell 2012;22:631–44.