Abstract
MYCN amplification predicts poor prognosis and resistance to therapy in human neuroblastoma. However, pharmacological strategies that directly antagonize MYCN, the protein encoded by MYCN, remain unsuccessful. Oncogenic MYCN regulates many aspects of cellular metabolism, which in principle provides novel targets for development of effective cancer therapeutics. We herein identified the solute carrier family 25 member 1 (SLC25A1)-mediated mitochondrial citrate export as a metabolic vulnerability in MYCN-amplified neuroblastomas. The citrate efflux from mitochondria is essential for MYCN-amplified neuroblastoma cells to generate the necessary acetyl-CoA to support histone acetylation and subsequent transcriptional activation of the anti-apoptotic baculoviral IAP repeat containing 3 (BIRC3) gene. Meanwhile, elevated cytosolic acetyl-CoA sustains the acetylation of non-histone protein myeloid cell leukemia 1 (MCL1), which counteracts its protein degradation by the 26S proteasome. BIRC3 and MCL1 in turn cooperate to inhibit apoptosis in MYCN-amplified neuroblastoma cells. Inhibition of SLC25A1 preferentially induced potent apoptosis in MYCN-amplified neuroblastoma cells, and synergistically potentiated the therapeutic efficacies of BCL2 antagonists. These findings reveal SLC25A1 as an actionable MYCN-driven metabolic liability, and validate SLC25A1 inhibitors, alone or in combination with BCL2 antagonists, as potential effective therapeutics for MYCN-amplified neuroblastomas.