Loss of MCL1 function sensitizes the MDA‐MB‐231 breast cancer cells to rh‐TRAIL by increasing DR4 levels

Blasio, Anna De; Pratelli, Giovanni; Drago-Ferrante, Rosa; Saliba, Christian; Baldacchino, Shawn; Grech, Godfrey; Tesoriere, Giovanni; Scerri, Christian; Vento, Renza; Fiore, Riccardo Di

doi:10.1002/jcp.28479

Cited by 9 publications

(8 citation statements)

References 33 publications

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“…Alternative approaches that induce Mcl1 proteasomal degradation (by GDC-094 treatments, for example), have also been effective in overcoming resistance, thus allowing ABT-737 to have greater effects against BC cells [ 346 ] and lung cancer (LC) cells [ 106 ]. Similar effects have also been reported for Mcl1 inhibition and TRAIL co-stimulation of BC cells [ 338 ]. Conversely, stabilization of Mcl1 protein by BAG3 and survival of BC and PC cells under ABT-737 stimulatory conditions has also been reported [ 105 ], highlighting a central but indirect and positive regulatory mechanism for the Mcl1 protein as a therapeutic resistance factor.…”

Section: Main Textsupporting

confidence: 86%

BH3-mimetics: recent developments in cancer therapy

Townsend

Kozhevnikova

Cexus

et al. 2021

J Exp Clin Cancer Res

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The hopeful outcomes from 30 years of research in BH3-mimetics have indeed served a number of solid paradigms for targeting intermediates from the apoptosis pathway in a variety of diseased states. Not only have such rational approaches in drug design yielded several key therapeutics, such outputs have also offered insights into the integrated mechanistic aspects of basic and clinical research at the genetics level for the future. In no other area of medical research have the effects of such work been felt, than in cancer research, through targeting the BAX-Bcl-2 protein-protein interactions. With these promising outputs in mind, several mimetics, and their potential therapeutic applications, have also been developed for several other pathological conditions, such as cardiovascular disease and tissue fibrosis, thus highlighting the universal importance of the intrinsic arm of the apoptosis pathway and its input to general tissue homeostasis. Considering such recent developments, and in a field that has generated so much scientific interest, we take stock of how the broadening area of BH3-mimetics has developed and diversified, with a focus on their uses in single and combined cancer treatment regimens and recently explored therapeutic delivery methods that may aid the development of future therapeutics of this nature.

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Section: Main Textsupporting

confidence: 86%

BH3-mimetics: recent developments in cancer therapy

Townsend

Kozhevnikova

Cexus

et al. 2021

J Exp Clin Cancer Res

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“…One way MCL1 contributes to AML relapse is by promoting resistance to certain treatments. For example, MCL1 has been found to be differentially expressed in triple-negative breast cancer (TNBC) tissues and cells, potentially limiting the efficacy of anticancer agents like recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rh-TRAIL) [35]. In AML, MCL1 downregulation has been observed when CDK7 inhibitor THZ1 is combined with azacitidine (AZA), resulting in synergistic antileukemic effects in AML cell lines and primary cells [36].…”

Section: Discussionmentioning

confidence: 99%

Predictive Power of Machine Learning Models for Relapse Outcomes in Acute Myeloid Leukemia: Unveiling Key Genes and Pathways for Improved Patient Management

Radak,

Fallahi,

Karami

2023

Preprint

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Acute Myeloid Leukemia (AML) is a challenging form of blood cancer requiring accurate relapse prediction for effective therapy and patient management. In this study, we applied multiple machine learning techniques to a dataset of AML patients in order to develop a reliable model for predicting relapse and guiding treatment decisions. We utilized various feature selection methods to identify the most relevant features associated with relapse. Additionally, we investigated gene ontology using the Gene Ontology (GO) database to gain insights into the biological processes and KEGG pathways related to the selected features. Our findings revealed key genes and pathways implicated in AML relapse. Among the machine learning models, Decision Tree (DT) showed the highest accuracy in predicting relapse outcomes. Furthermore, we compared the performance of DT models across different feature selections, highlighting the significance of specific factors such as MCL1, WBC, HGB, and BAD.p112 in relapse prediction. The results of our study have important implications for tailoring treatment plans and improving patient outcomes in AML. By accurately identifying patients at high risk of relapse, our model can aid in early interventions and personalized therapies. Ultimately, our research contributes to advancing the field of machine learning in AML and lays the foundation for developing effective strategies to combat relapse in this disease.

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“…Treatments targeting MCL1 could be an effective strategy to overcome rh-TRAIL resistance in Triple Negative Breast Cancer (TNBC). 19 Other studies also identified the essential role of Mcl-1 in promoting chemoresistance and showed that Mcl-1 could be a promising target for the treatment of ovarian cancer. 18,20 MicroRNAs (miRNAs) are small noncoding RNAs (21-25 nucleotides) that act post-transcriptionally to suppress gene expression.…”

Section: Discussionmentioning

confidence: 99%

<p>A Chemotherapy-Driven Increase in Mcl-1 Mediates the Effect of miR-375 on Cisplatin Resistance in Osteosarcoma Cells</p>

Liu¹,

Yu²,

Yang³

et al. 2019

OTT

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Background: Osteosarcoma (OS) is one of the most difficult cancers to treat due to its resistance to chemotherapy. The essential role played by Mcl-1 in promoting chemoresistance has been observed in a variety of cancers, including OS, while the underlying mechanism remains unclear. Methods: We investigated the expression of Mcl-1 in 42 paired OS specimens obtained before and after adjuvant chemotherapy, and its correlation with clinicopathological characteristics. Loss and gain of function studies were performed to analyze the effects of Mcl-1 modulations on the chemosensitivity, and the mechanism involved in the deregulation of Mcl-1 in OS cells. Results: In OS specimens, the expression of Mcl-1 was significantly upregulated after chemotherapy, and high Mcl-1 expression was associated with poorer overall survival and an increased recurrence rate. Furthermore, we demonstrated that chemotherapy-driven increased Mcl-1 decreased chemosensitivity by promoting tumour proliferation and inhibiting DNA damage. Moreover, Mcl-1 was found to be a direct target of miR-375 in OS cells. The knockdown of Mcl-1 phenocopied miR-375 downregulation, and the overexpression of miR-375 rescued the effects of cisplatin-induced DNA damage mediated by Mcl-1. Conclusion: Our data indicated that chemotherapy-driven increase in the expression of Mcl-1 plays a critical role in chemoresistance, and the intervention of the miR-375/Mcl-1 axis may offer a novel strategy to enhance chemosensitivity in OS treatment.

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Loss of MCL1 function sensitizes the MDA‐MB‐231 breast cancer cells to rh‐TRAIL by increasing DR4 levels

Cited by 9 publications

References 33 publications

BH3-mimetics: recent developments in cancer therapy

BH3-mimetics: recent developments in cancer therapy

Predictive Power of Machine Learning Models for Relapse Outcomes in Acute Myeloid Leukemia: Unveiling Key Genes and Pathways for Improved Patient Management

<p>A Chemotherapy-Driven Increase in Mcl-1 Mediates the Effect of miR-375 on Cisplatin Resistance in Osteosarcoma Cells</p>

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