MCL-1 dependency as a novel vulnerability for aggressive B cell lymphomas

Wang, Michelle; Li, Tao; Ren, Yuan; Shah, Bijal; Lwin, Tint; Gao, Jing; Shain, Kenneth H.; Zhang, Wei; Zhao, Xiaohong; Tao, Jianguo

doi:10.1038/s41408-020-00402-2

Cited by 6 publications

(4 citation statements)

References 15 publications

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“…BH3-mimetic drugs targeting related pro-survival BCL-2 proteins have also been developed for cancer therapy. A wealth of evidence supports the notion that MCL-1 inhibitors would be efficacious for a broad range of haematological malignancies, including for aggressive MYC-driven lymphomas, such as Burkitt Lymphomas (BL), which are known to be highly dependent on MCL-1 for continued survival and proliferation [10][11][12][13][14][15][16]. Such MYCdriven lymphomas can be modelled pre-clinically using the Eµ-Myc transgenic mouse model, which recapitulates the immunoglobulin/c-MYC chromosomal translocation characteristic of BL, and results in pre-B/B cell lymphomas with almost 100% incidence [17].…”

Section: Introductionmentioning

confidence: 99%

Lymphoma cells lacking pro-apoptotic BAX are highly resistant to BH3-mimetics targeting pro-survival MCL-1 but retain sensitivity to conventional DNA-damaging drugs

et al. 2023

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BH3-mimetic drugs are an anti-cancer therapy that can induce apoptosis in malignant cells by directly binding and inhibiting pro-survival proteins of the BCL-2 family. The BH3-mimetic drug venetoclax, which targets BCL-2, has been approved for the treatment of chronic lymphocytic leukaemia and acute myeloid leukaemia by regulatory authorities worldwide. However, while most patients initially respond well, resistance and relapse while on this drug is an emerging and critical issue in the clinic. Though some studies have begun uncovering the factors involved in resistance to BCL-2-targeting BH3-mimetic drugs, little focus has been applied to pre-emptively tackle resistance for the next generation of BH3-mimetic drugs targeting MCL-1, which are now in clinical trials for diverse blood cancers. Therefore, using pre-clinical mouse and human models of aggressive lymphoma, we sought to predict factors likely to contribute to the development of resistance in patients receiving MCL-1-targeting BH3-mimetic drugs. First, we performed multiple whole genome CRISPR/Cas9 KO screens and identified that loss of the pro-apoptotic effector protein BAX, but not its close relative BAK, could confer resistance to MCL-1-targeting BH3-mimetic drugs in both short-term and long-term treatment regimens, even in lymphoma cells lacking the tumour suppressor TRP53. Furthermore, we found that mouse Eµ-Myc lymphoma cells selected for loss of BAX, as well as upregulation of the untargeted pro-survival BCL-2 family proteins BCL-XL and A1, when made naturally resistant to MCL-1 inhibitors by culturing them in increasing doses of drug over time, a situation mimicking the clinical application of these drugs. Finally, we identified therapeutic approaches which could overcome these two methods of resistance: the use of chemotherapeutic drugs or combined BH3-mimetic treatment, respectively. Collectively, these results uncover some key factors likely to cause resistance to MCL-1 inhibition in the clinic and suggest rational therapeutic strategies to overcome resistance that should be investigated further.

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Section: Introductionmentioning

confidence: 99%

Lymphoma cells lacking pro-apoptotic BAX are highly resistant to BH3-mimetics targeting pro-survival MCL-1 but retain sensitivity to conventional DNA-damaging drugs

et al. 2023

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“…Molecular docking analysis on coumarin compounds showed significant binding affinities toward certain protein targets that have a critical function in the maintenance of DLBCL cell proliferation and survival (Table III) [38][39][40]. The results indicated that the compounds 2 and 3 formed the most significant complexes with unphosphorylated protein kinase B/Akt (PDB ID: 1GZO) with binding values lower than -10.00 kcal/mol.…”

Section: Analysis Of Binding Affinities Of Coumarin Compoundsmentioning

confidence: 99%

“…Deregulation of the antiapoptotic B-cell lymphoma 2 (BCL-2) protein family, including Mcl-1 is linked with lymphomagenesis and resistance to chemotherapeutic drugs. Mcl-1 promotes the progression survival of lymphoma cells by counteracting the activity of pro-apoptotic proteins [40]. Molecular docking data indicate that candidate compounds 2 and 1 form strong complexes with Mcl-1 protein (PDB ID: 6B4L), suggesting that the potential antitumor effect of the mentioned substances should be further evaluated.…”

Section: Analysis Of Binding Affinities Of Coumarin Compoundsmentioning

confidence: 99%

Synthesis, in Silico Study and Antitumor Activity of Coumarin Compounds in Lymphoma Cells

BILAJAC

2023

FARMACIA

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Coumarin derivatives are characterised by a wide range of therapeutic applications, including anti-tumour activity. Using in silico and in vitro approaches, we evaluated the possible antitumor effects of four 3-cinnamoyl-4-hydroxycoumarin derivatives in diffuse large B-cell lymphoma (DLBCL) cells.. Also, molecular properties and several ADME parameters were our subjects of investigation. The results of an in silico molecular docking analysis show that coumarin compounds have a strong affinity for binding to Akt, NF-κB and Mcl-1 protein targets, which are important for controlling the growth, differentiation and survival of DLBCL cells. Analysed molecular and ADME properties show that compounds satisfy Lipinski's rule of five. The WST-8 test showed that coumarin derivatives with bromine substituents had a strong cytotoxic effect on HBL-1 cells, which are a type of more aggressive activated B-cell (ABC) DLBCL. However, treatment of DHL-4 germinal centre B-cell (GCB) DLBCL cells with the same substanceshowed no inhibitory activity, suggesting diverse mechanism of action among two distinct DLBCL models.Western blot analysis indicated stimulatory activity of compound 2, with increased Akt phosphorylation levels in both types of cells. These results represent an insight into the activation of the compensatory Akt mechanisms in DLBCL cells. This could represent a key step in combinatorial treatment approaches in order to avoid drug resistance and achieve greater therapeutic efficacy in DLBCL cells. RezumatDerivații cumarinici se caracterizează printr-o gamă largă de acțiuni terapeutice, incluzând activitatea antitumorală. În cadrul acestui studiu, a fost investigată in silico și in vitro potențiala activitate antitumorală în limfomul difuz cu celule B mari (DLBCL) și descrisă farmacocinetica pentru patru derivați sintetizați de 3-cinamoil-4-hidroxicumarină. Datele analizei in silico sugerează afinități puternice de legare a compușilor cumarinici față de țintele proteice Akt, NF-κB și Mcl-1 ca regulatori principali ai proliferării, diferențierii și supraviețuirii celulelor DLBCL. Rezultatele analizei WST-8 au arătat un efect citotoxic puternic al derivatului de cumarină cu substituent de brom în celulele HBL-1 ce aparțin subtipului mai agresiv DLBCL al celulei B activate. Cu toate acestea, în cazul tratării celulelor DLBCL din centrul germinal B (GCB) DHL-4 cu aceeași substanță nu s-a observat nicio activitate inhibitorie, sugerându-se astfel un alt mecanism de acțiune. Analiza Western Blot a demonstrat activitatea stimulatoare a compusului 2, cu niveluri crescute de fosforilare a Akt. Rezultatele studiului oferă o mai bună înțelegere a modului în care funcționează mecanismul compensator Akt în celulele DLBCL. Acesta ar putea fi un pas esențial în găsirea unor noi abordări terapeutice a celulelor DLBCL rezistente la tratament.

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“…Several key oncogenic pathways lead to increased MCL-1 protein expression through transcriptional or post-transcriptional mechanisms 14 . Studies employing genetic silencing or inducible expression of ligands that inhibit MCL-1 demonstrate its essentiality in the growth of multiple tumor types including multiple myeloma (MM) 15 , AML 16 , and non-Hodgkin lymphoma 17 . Literature data support a role for MCL-1 as a resistance factor to anticancer therapies such as gemcitabine 18 , vincristine, and paclitaxel 19 .…”

Section: Introductionmentioning

confidence: 99%

Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients

Yuda,

Will,

Phillips

et al. 2023

Commun Med

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Background MCL-1 is a prosurvival B-cell lymphoma 2 family protein that plays a critical role in tumor maintenance and survival and can act as a resistance factor to multiple anticancer therapies. Herein, we describe the generation and characterization of the highly potent and selective MCL-1 inhibitor ABBV-467 and present findings from a first-in-human trial that included patients with relapsed/refractory multiple myeloma (NCT04178902). Methods Binding of ABBV-467 to human MCL-1 was assessed in multiple cell lines. The ability of ABBV-467 to induce tumor growth inhibition was investigated in xenograft models of human multiple myeloma and acute myelogenous leukemia. The first-in-human study was a multicenter, open-label, dose-escalation study assessing safety, pharmacokinetics, and efficacy of ABBV-467 monotherapy. Results Here we show that administration of ABBV-467 to MCL-1-dependent tumor cell lines triggers rapid and mechanism-based apoptosis. In vivo, intermittent dosing of ABBV-467 as monotherapy or in combination with venetoclax inhibits the growth of xenografts from human hematologic cancers. Results from a clinical trial evaluating ABBV-467 in patients with multiple myeloma based on these preclinical data indicate that treatment with ABBV-467 can result in disease control (seen in 1 patient), but may also cause increases in cardiac troponin levels in the plasma in some patients (seen in 4 of 8 patients), without other corresponding cardiac findings. Conclusions The selectivity of ABBV-467 suggests that treatment-induced troponin release is a consequence of MCL-1 inhibition and therefore may represent a class effect of MCL-1 inhibitors in human patients.

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MCL-1 dependency as a novel vulnerability for aggressive B cell lymphomas

Cited by 6 publications

References 15 publications

Lymphoma cells lacking pro-apoptotic BAX are highly resistant to BH3-mimetics targeting pro-survival MCL-1 but retain sensitivity to conventional DNA-damaging drugs

Lymphoma cells lacking pro-apoptotic BAX are highly resistant to BH3-mimetics targeting pro-survival MCL-1 but retain sensitivity to conventional DNA-damaging drugs

Synthesis, in Silico Study and Antitumor Activity of Coumarin Compounds in Lymphoma Cells

Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients

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