The EACR’s Top 10 Cancer Research Publications is a regular summary of the most interesting and impactful recent papers in cancer research. It is curated by the Board of the European Association for Cancer Research (EACR).
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Garciaz et al., Cancer Discov January 26 2022 DOI: 10.1158/2159-8290.CD-21-0522
Brief summary of the findings
Identifying new mechanisms inducing cancer cell death is critical for improving clinical outcomes. Ironomycin is a salinomycin-derivative drug that sequesters iron into the lysosomes and induces a non-apoptotic death in cancer cells. Using unbiased CRISPR screening, we studied the effect of ironomycin in acute myeloid leukemia (AML) cells. We surprisingly found that mitochondrial metabolism was the main modulator of ironomycin efficacy. Using a multidisciplinary systems biology approach including metabolomics, RNA sequencing, video-microscopy ICP-mass spectrometry and functional testing, we observed that the drug induced a strong depletion in mitochondrial iron triggering a defect in mitochondrial respiration and a mitochondrial stress response. Ironomycin treatment induced a BAX/BAK-dependent mitochondrial outer membrane permeabilization (MOMP) leading to cell death. Contrary to venetoclax, a BH3-mimetics commonly used for AML treatment, BAX and BAK activation was independent on the anti-apoptotic protein BCL-2 or the BH3-only pro-apoptotic proteins. Interestingly, this non-canonical new cell death modality potentiated the effect of venetoclax in vivo and was independent of AML cells TP53 status. Finally, the drug was active in venetoclax resistant leukemia cells derived from patients. In conclusion, ironomycin inexorably links mitochondrial metabolism to cell death and represents a new therapeutics for treating cancer cells resistant to BH3-mimetics.
Future impact of the findings
Acute myeloid leukemia patients with AML blasts that are resistant to the BH3-mimetics venetoclax have an extremely poor outcome. Ironomycin reduces mitochondrial iron, starves mitochondria and provokes a BAX/BAK dependent cell death non-redundant with BH3-mimetics. Triggering this new cell death modality can resensitize resistant AML cells to the BH3-mimetics venetoclax and overcome BH3-mimetics resistance. Ironomycin represents a new bullet in the fight against aggressive leukemias, by inducing non-canonical cell death in AML patients resistant to BH3-mimetics.
