Kim, J. W.; Bebber, C. M.; Dai, Y.; Bopp, S.; Edenhofer, A.; Li, A. M.; Rosner, T.; Berning, L.; Yang, M.; Leak, L. B.; Stroh, J.; Shrestha, B.; Abdallah, A.; Prymidis, D.; Olivos, H.; Baron, M.; Nguyen, T.; Shue, Y. T.; Nishiga, Y.; Drainas, A.; Chaikovsky, A.; Szylo, K.; Li, Y.; Kang, Y. P.; Manoj, P.; Quintanal Villalonga, A.; Rudin, C. M.; DeNicola, G. M.; Dixon, S. J.; Frezza, C.; Ye, J.; von Karstedt, S.; Sage, J.

Cellular heterogeneity and plasticity are hallmarks of cancer that contribute to tumor growth and therapy resistance. Here we investigated metabolic heterogeneity in small cell lung cancer (SCLC), an aggressive neuroendocrine (NE) cancer type. Through integrated transcriptomic and metabolomic analyses, we identified a universal dependency on exogenous cysteine/cystine (Cys) across all NE/non-NE SCLC cell states. Notably, NE and non-NE cells with low levels of the ASCL1 transcription factor die from ferroptosis upon Cys depletion. In contrast, ASCL1-high cells die from apoptosis but are ferroptosis resistant. This resistance to ferroptosis is driven by the direct upregulation of the gene coding for the GCH1 enzyme by ASCL1, which results in higher levels of the BH4/BH2 antioxidants. Accordingly, combining cysteine depletion with BH4/BH2 synthesis inhibition effectively reduces tumor growth in patient-derived xenografts. This work elucidates distinct metabolic states in SCLC and suggests new approaches to induce cell death in this lethal form of cancer.