Multiple BCL2 mutations cooccurring with Gly101Val emerge in chronic lymphocytic leukemia progression on venetoclax

Blombery, Piers; Thompson, Ella R.; Nguyen, Tamia; Birkinshaw, R.W.; Gong, Jianan; Chen, Xiangting; McBean, Michelle; Thijssen, Rachel; Conway, Thomas; Anderson, Mary Ann; Seymour, John F.; Westerman, David; Czabotar, P.E.; Huang, David C.S.; Roberts, Andrew W.

doi:10.1182/blood.2019004205

Cited by 119 publications

(118 citation statements)

References 20 publications

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“…This mutation was independently reported by another team, along a second one (D103Y) [37]. Additional BCL2 mutations acquired in parallel with BCL-2 G101V were recently reported in patients with progressive CLL on venetoclax [38]. Acquired BCL-2 mutations have also been described in MCL, but recent studies suggested that they are infrequent [39].…”

Section: Mechanism Of Acquired Intrinsic Resistancementioning

confidence: 80%

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

Jullien

Gomez‐Bougie

Chiron

et al. 2020

Cells

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Apoptosis is a highly conserved mechanism enabling the removal of unwanted cells. Mitochondrial apoptosis is governed by the B-cell lymphoma (BCL-2) family, including anti-apoptotic and pro-apoptotic proteins. Apoptosis evasion by dysregulation of anti-apoptotic BCL-2 members (BCL-2, MCL-1, BCL-X L ) is a common hallmark in cancers. To divert this dysregulation into vulnerability, researchers have developed BH3 mimetics, which are small molecules that restore effective apoptosis in neoplastic cells by interfering with anti-apoptotic proteins. Among them, venetoclax is a potent and selective BCL-2 inhibitor, which has demonstrated the strongest clinical activity in mature B-cell malignancies, including chronic lymphoid leukemia, mantle-cell lymphoma, and multiple myeloma. Nevertheless, mechanisms of primary and acquired resistance have been recently described and several features such as cytogenetic abnormalities, BCL-2 family expression, and ex vivo drug testing have to be considered for predicting sensitivity to BH3 mimetics and helping in the identification of patients able to respond. The medical need to overcome resistance to BH3 mimetics supports the evaluation of innovative combination strategies. Novel agents including MCL-1 targeting BH3 mimetics are currently evaluated and may represent new therapeutic options in the field. The present review summarizes the current knowledge regarding venetoclax and other BH3 mimetics for the treatment of mature B-cell malignancies.

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Section: Mechanism Of Acquired Intrinsic Resistancementioning

confidence: 80%

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

Jullien

Gomez‐Bougie

Chiron

et al. 2020

Cells

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“…The mutation, which reduces the affinity of venetoclax for BCL2 and confers acquired resistance in vitro and in vivo, was present in 7 of 15 paired samples at progression but not at treatment initiation [127]. Moreover, multiple novel BCL2 mutations have been recently identified in parallel with BCL2 Gly101Val during venetoclax therapy [128,129].…”

Section: Bcl2 Mutationsmentioning

confidence: 99%

An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy

Cohen

Bomben

Pozzo

et al. 2020

Cancers

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Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course. Novel biomarkers discovered over the past 20 years have revolutionized the way clinicians approach prognostication and treatment especially in the chemotherapy-free era. Herein, we review the best established prognostic and predictive biomarkers in the setting of chemoimmunotherapy (CIT) and novel targeted therapy. We propose that TP53 disruption (defined as either TP53 mutation or chromosome 17p deletion), unmutated immunoglobulin heavy chain variable region gene status (UM IGHV), NOTCH1 mutation, and CD49d expression are the strongest prognosticators of disease progression and overall survival in the field of novel biomarkers including recurrent gene mutations. We also highlight the predictive role of TP53 disruption, UM IGHV, and NOTCH1 mutation in the setting of CIT and TP53 disruption and CD49d expression in the setting of novel targeted therapy employing B-cell receptor (BCR) and B-cell lymphoma-2 (BCL2) inhibition. Finally, we discuss future directions in the field of biomarker development to identify those with relapsed/refractory disease at risk for progression despite treatment with novel therapies.

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“…However, many patients do not respond or initially respond but subsequently progress. Resistance to venetoclax appears to be primarily caused by mutations in Bcl-2 or compensatory overexpression of Mcl-1 and other antiapoptotic Bcl-2-family members 28,35,[53][54][55][56][57] . In addition, Bcl-2 phosphorylation at Ser70 has been shown to induce a structural alteration in the BH3-binding groove that reduces by 100-300-fold the binding affinity of venetoclax 39 .…”

Section: Discussionmentioning

confidence: 99%

BDA-366, a putative Bcl-2 BH4 domain antagonist, induces apoptosis independently of Bcl-2 in a variety of cancer cell models

et al. 2020

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Several cancer cell types, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL) upregulate antiapoptotic Bcl-2 to cope with oncogenic stress. BH3 mimetics targeting Bcl-2’s hydrophobic cleft have been developed, including venetoclax as a promising anticancer precision medicine for treating CLL patients. Recently, BDA-366 was identified as a small molecule BH4-domain antagonist that could kill lung cancer and multiple myeloma cells. BDA-366 was proposed to switch Bcl-2 from an antiapoptotic into a proapoptotic protein, thereby activating Bax and inducing apoptosis. Here, we scrutinized the therapeutic potential and mechanism of action of BDA-366 in CLL and DLBCL. Although BDA-366 displayed selective toxicity against both cell types, the BDA-366-induced cell death did not correlate with Bcl-2-protein levels and also occurred in the absence of Bcl-2. Moreover, although BDA-366 provoked Bax activation, it did neither directly activate Bax nor switch Bcl-2 into a Bax-activating protein in in vitro Bax/liposome assays. Instead, in primary CLL cells and DLBCL cell lines, BDA-366 inhibited the activity of the PI3K/AKT pathway, resulted in Bcl-2 dephosphorylation and reduced Mcl-1-protein levels without affecting the levels of Bcl-2 or Bcl-xL. Hence, our work challenges the current view that BDA-366 is a BH4-domain antagonist of Bcl-2 that turns Bcl-2 into a pro-apoptotic protein. Rather, our results indicate that other mechanisms beyond switching Bcl-2 conformation underlie BDA-366’s cell-death properties that may implicate Mcl-1 downregulation and/or Bcl-2 dephosphorylation.

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Multiple BCL2 mutations cooccurring with Gly101Val emerge in chronic lymphocytic leukemia progression on venetoclax

Cited by 119 publications

References 20 publications

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy

BDA-366, a putative Bcl-2 BH4 domain antagonist, induces apoptosis independently of Bcl-2 in a variety of cancer cell models

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