Targeting Mcl-1 and other Bcl-2 family member proteins in cancer therapy

Yamaguchi, Ryuji; Lartigue, Lydia; Perkins, Guy

doi:10.1016/j.pharmthera.2018.10.009

Cited by 78 publications

(45 citation statements)

References 74 publications

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“…Bcl-2 family proteins are well-known important regulators of the mitochondrial apoptotic pathway, through keeping the balance between pro-and antiapoptotic proteins. The (26)(27)(28)(29). In the present study, Bcl-2 and Bcl-xL expression levels were upregulated in the osimertinib-resistant cell line compared with the sensitive parent cell line.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Bcl-2 and Bcl-xL overcomes the resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer

Bian

Zhang

et al. 2020

Mol Med Rep

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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated significant benefits to patients with non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations; however, acquired resistance limits their long-term efficacy. Therefore, it remains an urgent requirement to discover the underlying mechanisms and investigate novel therapeutic strategies for overcoming the resistance to EGFR TKIs. The present study aimed to determine the mechanism underlying the resistance of NSCLC cells to osimertinib, a third-generation EGFR tyrosine kinase inhibitor, the osimertinib-resistant NSCLC cell sub-line HCC827/OR was established in the present study. It was found that the expression levels of Bcl-2 and Bcl-xL were significantly upregulated in resistant cells compared with sensitive cells. Furthermore, the suppression of Bcl-2 and Bcl-xL through small interfering RNA-mediated gene knockdown or using a small molecule specific inhibitor ABT-263 re-sensitized HCC827/OR cells to osimertinib treatment. Moreover, the combined treatment of HCC827/OR cells with ABT-263 and osimertinib enhanced the rate of cell apoptosis through the mitochondrial apoptotic pathway. Finally, ABT-263 was able to overcome the resistance of osimertinib in xenograft tumor models. In conclusion, these findings may provide an improved concept for the development of a novel combined therapeutic strategy for the treatment of NSCLC resistance to EGFR TKIs.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Bcl-2 and Bcl-xL overcomes the resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer

Bian

Zhang

et al. 2020

Mol Med Rep

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“…Apoptosis evasion is an important hallmark of cancers 64 and limits the efficacy of CDDP. 6,7 Although Mcl-1 has received much attention due to its unique role in mediating apoptosis and chemoresistance, 11,65,66 Pt IV complexes targeting Mcl-1, and further targeting RAD51 and BRCA2 have not been reported so far. This study provides uncommon examples of the design of such complexes; also, it gives some new insight into the cytostatic mechanism of such complexes and broadens the way to designing Pt complexes for overcoming CDDP resistance.…”

Section: Discussionmentioning

confidence: 99%

Interfering in apoptosis and DNA repair of cancer cells to conquer cisplatin resistance by platinum(iv) prodrugs

et al. 2020

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“…45,46 Newly developed inhibitors of the BCL2 family are proving effective against haematological malignancies but are yet to define a role against solid cancers. 47,48 In the case of melanoma, practically all anti-apoptotic members appear to be involved but with varying importance in individual tumours. MCL1…”

Section: Discussionmentioning

confidence: 99%

Co‐targeting bromodomain and extra‐terminal proteins and MCL1 induces synergistic cell death in melanoma

Tseng

Dreyer

Emran

et al. 2020

Intl Journal of Cancer

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The treatment of melanoma has been markedly improved by the introduction of targeted therapies and checkpoint blockade immunotherapy. Unfortunately, resistance to these therapies remains a limitation. Novel anticancer therapeutics targeting the MCL1 anti‐apoptotic protein have shown impressive responses in haematological cancers but are yet to be evaluated in melanoma. To assess the sensitivity of melanoma to new MCL1 inhibitors, we measured the response of 51 melanoma cell lines to the novel MCL1 inhibitor, S63845. Additionally, we assessed combination of this drug with inhibitors of the bromodomain and extra‐terminal (BET) protein family of epigenetic readers, which we postulated would assist MCL1 inhibition by downregulating anti‐apoptotic targets regulated by NF‐kB such as BCLXL, BCL2A1 and XIAP, and by upregulating pro‐apoptotic proteins including BIM and NOXA. Only 14% of melanoma cell lines showed sensitivity to S63845, however, combination of S63845 and I‐BET151 induced highly synergistic apoptotic cell death in all melanoma lines tested and in an in vivo xenograft model. Cell death was dependent on caspases and BAX/BAK. Although the combination of drugs increased the BH3‐only protein, BIM, and downregulated anti‐apoptotic proteins such as BCL2A1, the importance of these proteins in inducing cell death varied between cell lines. ABT‐199 or ABT‐263 inhibitors against BCL2 or BCL2 and BCLXL, respectively, induced further cell death when combined with S63845 and I‐BET151. The combination of MCL1 and BET inhibition appears to be a promising therapeutic approach for metastatic melanoma, and presents opportunities to add further BCL2 family inhibitors to overcome treatment resistance.

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Targeting Mcl-1 and other Bcl-2 family member proteins in cancer therapy

Cited by 78 publications

References 74 publications

Inhibition of Bcl-2 and Bcl-xL overcomes the resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer

Inhibition of Bcl-2 and Bcl-xL overcomes the resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer

Interfering in apoptosis and DNA repair of cancer cells to conquer cisplatin resistance by platinum(iv) prodrugs

Co‐targeting bromodomain and extra‐terminal proteins and MCL1 induces synergistic cell death in melanoma

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