Certain childhood tumors have an extreme need for amino acids. We together with scientists at the Hopp Children's Cancer Center Heidelberg (KiTZ), the German Cancer Research Center (DKFZ) and the University of Heidelberg, have now discovered the molecular mechanisms underlying this and how the cancer cells could be turned off.
Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. The high cysteine demand of MYCN-amplified childhood neuroblastoma is met by uptake and transsulfuration. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of GSH triggering ferroptosis and potentially contributing to spontaneous tumor regression in low-risk neuroblastomas. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. These findings provide a proof of concept of combining multiple ferroptosis targets as a promising therapeutic strategy for aggressive MYCN-amplified tumors.
Alborzinia H, Flórez A.F., Kreth S., Brückner L.M. et al. MYCN mediates cysteine addiction and sensitizes neuroblastoma to Ferroptosis In: Nature Cancer 2022, DOI: 10.1038/s43018-022-00355-4