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APR-246 induced ferroptosis in AM
sis induction to treat cancer is an emerging field in oncol- ogy research. Renal cancer cells have been reported as highly dependent on the GSH pathway for ROS detoxifi- cation, including lipid peroxides, and targeting compo- nents of this pathway is an effective strategy for the treat- ment of this disease.41 Other studies have elegantly high- lighted the higher sensitivity to ferroptosis of cancer cells that are resistant to conventional therapy.42,43 In AML, data about ferroptosis are scarce. An in vitro study showed that the ferroptosis inducer erastin enhances sensitivity of AML cells to chemotherapeutic agents.44 Jones et al. recently reported that cysteine depletion leads to GSH exhaustion and ROS-low leukemic stem cell eradication in AML.45 Thus, APR-246 could act on these cell pools that are poorly sensitive to conventional therapy, and which are at the origin of frequent therapeutic failures in AML.
From a clinical perspective, this mechanism of action might be relevant. Indeed, iron chelators are frequently used for the treatment of iron overload due to red blood cell transfusions and dyserythropoïesis in MDS/AML patients. Several studies have reported beneficial effects of iron chelation therapy on overall survival in MDS patients with iron overload.46 However, iron chelators are recog- nized as canonical ferroptosis inhibitors. Therefore, cau- tion should be exercised regarding co-administration of iron chelators which may antagonize the anti-leukemic activity of APR-246, as we observed in vitro. Moreover, the phase II studies of APR-246 in MDS/AML reported the occurrence of neurological adverse events in over a third of patients treated with APR-246.10,11 Recently, ferroptosis has been implicated in the pathogenesis of several neuro- logical disorders, especially neurodegenerative disor- ders.47,48 One hypothesis could be that the neurological side effects observed after administration of APR-246 are linked to its ability to deplete GSH in neuronal cells. Consequently, anti-ferroptosis agents, such as iron chela- tors or vitamin E, could be valuable drugs to treat these side effects. Finally, our study highlights that ferroptosis
induction may represent a new target in AML, opening new therapeutic strategies based on disease-specific vul- nerabilities. The effect of ferroptosis induction-based treatments on normal hematopoietic cells and their value compared to standard-of-care AML therapies will be important to evaluate in the future.
Disclosures
No conflicts of interest to disclose.
Contributions
JD, LCA, EG, TH performed experiments; CL, JES, JT, NG and MG performed in vivo experiments; NC, OK and MF pro- vided AML samples; NC, PM, JES, NJ and JT analyzed the results and corrected the manuscript; RB performed experiments, analyzed data, and wrote the manuscript; DB designed and supervised the research program, analyzed data, and wrote the manuscript. All authors approved the final version of the manu- script.
Acknowledgments
We thank Alain Schmitt and the cell imagery department at the Cochin Institute for performing the transmission electron microscopy. We thank Tata Jojo for manuscript proofreading. We also thank the CYBIO cytometry-department at the Cochin Institute. We further thank Aprea Therapeutics for providing the APR-246 used in the in vivo study.
Funding
This work was supported by grants from the Association de Recherche Contre le Cancer (ARC; aides doctorales RB, grant n°DOC20170505807 and DOC20190508975; aides jeune chercheur TH, grant n°M2R20180507379), from the Institut National du Cancer (JD, grant n° ASC16046KSA), from the Ligue Nationale Contre le Cancer (LNCC; DB, Equipe Labellisée EL2017. N° Projet: ELFUZ17337; NG, grant n° IP/SCG/JD-16129) and from association Laurette Fugain (grant n°ALF2018/02).
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