Venetoclax-resistant CLL cells show a highly activated and proliferative phenotype

Elías, Esteban Enrique; Martínez, Valeria Judith Sarapura; Amondarain, Mikele; Colado, Ana; Cordini, Gregorio; Bezares, Raimundo F.; Grecco, Horacio Fernández; Custidiano, Maria Del Rosario; Ávalos, Julio César Sánchez; Garate, Gonzalo; Pavlovsky, Miguel Arturo; Borge, Mercedes; Giordano, Mirta; Gamberale, Romina

doi:10.1007/s00262-021-03043-x

Cited by 11 publications

(22 citation statements)

References 18 publications

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“…3,11 Moreover, venetoclax-resistant CLL cells harbored activation and proliferation features, which could explain the brief response in our patients with a high proliferative index. 12 Third, IGHV unmutated status, found in 8/9 R/R aCLL patients, is associated with faster growth kinetics in R-VEN patients reaching undetectable MRD. 13 In the era of targeted therapies, especially with venetoclax-based regimens, deep responses with undetectable MRD are achievable, yet in our cohort, these early responses did not translate into prolonged progression-free survival.…”

Section: F I G U R Ementioning

confidence: 96%

“Accelerated phase” chronic lymphocytic leukemia: Still an intermediate risk disease in the era of targeted therapies

Lapierre

Syrykh

Largeaud

et al. 2022

Hematological Oncology

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Section: F I G U R Ementioning

confidence: 96%

“Accelerated phase” chronic lymphocytic leukemia: Still an intermediate risk disease in the era of targeted therapies

Lapierre

Syrykh

Largeaud

et al. 2022

Hematological Oncology

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“…4 ) [ 49 – 51 ]. Moreover, these inhibitors may also directly target the microenvironment: in CLL patients, T-cell activation and proliferation is strongly reduced after inhibition of the BCR signalosome, thereby preventing T-cell-mediated upregulation of MCL-1 and BCL-X L in CLL cells and subsequent venetoclax resistance [ 52 ].…”

Section: Strategies To Overcome Primary and Secondary Venetoclax Resi...mentioning

confidence: 99%

Tipping the balance: toward rational combination therapies to overcome venetoclax resistance in mantle cell lymphoma

et al. 2022

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Mantle cell lymphoma (MCL), an aggressive, but incurable B-cell lymphoma, is genetically characterized by the t(11;14) translocation, resulting in the overexpression of Cyclin D1. In addition, deregulation of the B-cell lymphoma-2 (BCL-2) family proteins BCL-2, B-cell lymphoma-extra large (BCL-XL), and myeloid cell leukemia-1 (MCL-1) is highly common in MCL. This renders these BCL-2 family members attractive targets for therapy; indeed, the BCL-2 inhibitor venetoclax (ABT-199), which already received FDA approval for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), shows promising results in early clinical trials for MCL. However, a significant subset of patients show primary resistance or will develop resistance upon prolonged treatment. Here, we describe the underlying mechanisms of venetoclax resistance in MCL, such as upregulation of BCL-XL or MCL-1, and the recent (clinical) progress in the development of inhibitors for these BCL-2 family members, followed by the transcriptional and (post-)translational (dys)regulation of the BCL-2 family proteins, including the role of the lymphoid organ microenvironment. Based upon these insights, we discuss how rational combinations of venetoclax with other therapies can be exploited to prevent or overcome venetoclax resistance and improve MCL patient outcome.

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“…Importantly, targeting the anti-apoptotic protein BCL-2 by the antagonistic agent venetoclax is effective in relapsed CLL patients, including those with negative prognostic features [ 143 ]; however, venetoclax resistance development can be observed in some cases, potentially mediated through the compensatory upregulation of other anti-apoptotic proteins from the BCL-2 family. Sensitivity to venetoclax might be restored through treatment with SYK and PI3Kδ inhibitors, emphasizing the importance of combination therapy with novel agents as shown in a clinical study demonstrating the efficacy of BTK inhibitor therapy in venetoclax-resistant CLL patients [ 144 , 145 ].…”

Section: Potential Bypass Of Btk In the Vla-4 Signaling Activation Ca...mentioning

confidence: 99%

Integrin Signaling Shaping BTK-Inhibitor Resistance

Polcik

Prosseda

Pozzo

et al. 2022

Cells

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Integrins are adhesion molecules that function as anchors in retaining tumor cells in supportive tissues and facilitating metastasis. Beta1 integrins are known to contribute to cell adhesion-mediated drug resistance in cancer. Very late antigen-4 (VLA-4), a CD49d/CD29 heterodimer, is a beta1 integrin implicated in therapy resistance in both solid tumors and haematological malignancies such as chronic lymphocytic leukemia (CLL). A complex inside-out signaling mechanism activates VLA-4, which might include several therapeutic targets for CLL. Treatment regimens for this disease have recently shifted towards novel agents targeting BCR signaling. Bruton’s tyrosine kinase (BTK) is a component of B cell receptor signaling and BTK inhibitors such as ibrutinib are highly successful; however, their limitations include indefinite drug administration, the development of therapy resistance, and toxicities. VLA-4 might be activated independently of BTK, resulting in an ongoing interaction of CD49d-expressing leukemic cells with their surrounding tissue, which may reduce the success of therapy with BTK inhibitors and increases the need for alternative therapies. In this context, we discuss the inside-out signaling cascade culminating in VLA-4 activation, consider the advantages and disadvantages of BTK inhibitors in CLL and elucidate the mechanisms behind cell adhesion-mediated drug resistance.

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Venetoclax-resistant CLL cells show a highly activated and proliferative phenotype

Cited by 11 publications

References 18 publications

“Accelerated phase” chronic lymphocytic leukemia: Still an intermediate risk disease in the era of targeted therapies

“Accelerated phase” chronic lymphocytic leukemia: Still an intermediate risk disease in the era of targeted therapies

Tipping the balance: toward rational combination therapies to overcome venetoclax resistance in mantle cell lymphoma

Integrin Signaling Shaping BTK-Inhibitor Resistance

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