Cystine uptake inhibition potentiates front-line therapies in acute myeloid leukemia

Pardieu, Bryann; Pasanisi, Justine; Ling, Frank; Bello, Reinaldo Dal; Penneroux, Justine; Su, Angela; Joudinaud, Romane; Chat, Laureen; Wu, Hsin-Chieh; Duchmann, Matthieu; Sodaro, Gaetano; Chauvel, Clémentine; Castelli, Florence; Vasseur, Loïc; Pacchiardi, Kim; Belloucif, Yannis; Laiguillon, Marie-Charlotte; Meduri, Eshwar; Vaganay, Camille; Alexe, Gabriela; Berrou, Jeannig; Benaksas, Chaïma; Forget, Antoine; Braun, Thorsten; Gardin, Claude; Raffoux, Emmanuel; Clappier, Emmanuelle; Adès, Lionel; Thé, Hugues de; Fenaille, François; Huntly, Brian J. P.; Stegmaier, Kimberly; Dombret, Hervé; Fenouille, Nina; Lobry, Camille; Puissant, Alexandre; Itzykson, Raphaël

doi:10.1038/s41375-022-01573-6

Cited by 32 publications

(31 citation statements)

References 59 publications

(78 reference statements)

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“…There are three major approaches in development: (1) inhibiting MDM4 expression, with small molecule drugs and anti-sense targeting of spliceosome factors; (2) inhibiting p53-MDM4 interaction, predominantly using stapled-peptides; and (3) promoting MDM4 degradation, shown, for example, using Hsp90 inhibitor (17AAG) (as reviewed [24,68]). As relevant to our findings, blocking cystine uptake, most directly through SLC7A11 targeting, is being actively advanced for potentiating hematopoietic therapies [69]. It is also notable that blocking the multi-drug resistance pump 1 (MDR1, also known as P-glycoprotein or P-gp) is being explored for promoting eprenetapopt efficacy, though intracellular entrapment of glutathione-complexed drug to rationally target mutant p53 [70].…”

Section: Discussionsupporting

confidence: 58%

Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status

Mejía-Hernández

Raghu

Caramia

et al. 2022

Cancers

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Metastatic prostate cancer is a lethal disease in patients incapable of responding to therapeutic interventions. Invasive prostate cancer spread is caused by failure of the normal anti-cancer defense systems that are controlled by the tumour suppressor protein, p53. Upon mutation, p53 malfunctions. Therapeutic strategies to directly re-empower the growth-restrictive capacities of p53 in cancers have largely been unsuccessful, frequently because of a failure to discriminate responses in diseased and healthy tissues. Our studies sought alternative prostate cancer drivers, intending to uncover new treatment targets. We discovered the oncogenic potency of MDM4 in prostate cancer cells, both in the presence and absence of p53 and also its mutation. We uncovered that sustained depletion of MDM4 is growth inhibitory in prostate cancer cells, involving either apoptosis or senescence, depending on the cell and genetic context. We identified that the potency of MDM4 targeting could be potentiated in prostate cancers with mutant p53 through the addition of a first-in-class small molecule drug that was selected as a p53 reactivator and has the capacity to elevate oxidative stress in cancer cells to drive their death.

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Section: Discussionsupporting

confidence: 58%

Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status

Mejía-Hernández

Raghu

Caramia

et al. 2022

Cancers

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“…Ferroptosis inducers (FINs) belong to four classes [117] . Class I FINs include pharmacological agents that limit intracellular glutathione (GSH) through the inhibition of the system x ccystine/glutamate antiporter, as has been shown in non-leukemic models [28] .…”

Section: Ferroptosis Inducersmentioning

confidence: 99%

“…Class I FINs include pharmacological agents that limit intracellular glutathione (GSH) through the inhibition of the system x c - cystine/glutamate antiporter, as has been shown in non-leukemic models [ 28 ] . The main molecules of this class, which are active in AML models, are erastin and sulfasalazine [ 118 , 119 ] . Class II FINs directly inhibit the detoxifying enzyme GPX4.…”

Section: Rcd Inducers In Amlmentioning

confidence: 99%

Targeting regulated cell death pathways in acute myeloid leukemia

Garciaz¹,

Miller²,

Collette³

et al. 2023

Cancer Drug Resist

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The use of the BCL2 inhibitor venetoclax has transformed the management of patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. By triggering intrinsic apoptosis, the drug is an excellent illustration of how our greater understanding of molecular cell death pathways can be translated into the clinic. Nevertheless, most venetoclax-treated patients will relapse, suggesting the need to target additional regulated cell death pathways. To highlight advances in this strategy, we review the recognized regulated cell death pathways, including apoptosis, necroptosis, ferroptosis and autophagy. Next, we detail the therapeutic opportunities to trigger regulated cell death in AML. Finally, we describe the main drug discovery challenges for regulated cell death inducers and their translation into clinical trials. A better knowledge of the molecular pathways regulating cell death represents a promising strategy to develop new drugs to cure resistant or refractory AML patients, particularly those resistant to intrinsic apoptosis.

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“…Several studies have demonstrated increased xCT expression upon the surface of chemo-resistant tumor cells ( 83 ). Studies have found that SLC7A11 mutation was an independent risk factor of survival of AML patients ( 84 ). Thus, xCT could be a promising target for cancer therapy, especially when combined with other chemotherapy which increased ROS of tumor cells.…”

Section: Amino Acids In Hematologic Malignanciesmentioning

confidence: 99%

“…In AML patients with NPM1 mutations, Cys metabolism was upregulated with stronger cysteine dependency. Moreover, they found that sulfasalazine showed significant synergistic anti-leukemic effect with daunorubicin-cytarabine treatment in NPM1 -mutated AML samples and patient-derived xenograft models ( 84 ). Erastin, though previously proved to trigger ferroptosis, has been recently found to inhibit xCT ( 88 , 89 ).…”

Section: Amino Acids In Hematologic Malignanciesmentioning

confidence: 99%

Amino acids in hematologic malignancies: Current status and future perspective

Wang

Zhao

et al. 2023

Front. Nutr.

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In recent years, growing emphasis has been placed on amino acids and their role in hematologic malignancies. Cancer cell metabolism is altered during tumorigenesis and development to meet expanding energetic and biosynthetic demands. Amino acids not only act as energy-supplying substances, but also play a vital role via regulating key signaling pathways, modulating epigenetic factors and remodeling tumor microenvironment. Targeting amino acids may be an effective therapeutic approach to address the current therapeutic challenges. Here, we provide an updated overview of mechanisms by which amino acids facilitate tumor development and therapy resistance. We also summarize novel therapies targeting amino acids, focusing on recent advances in basic research and their potential clinical implications.

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Cystine uptake inhibition potentiates front-line therapies in acute myeloid leukemia

Cited by 32 publications

References 59 publications

Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status

Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status

Targeting regulated cell death pathways in acute myeloid leukemia

Amino acids in hematologic malignancies: Current status and future perspective

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