Loss in MCL-1 function sensitizes non-Hodgkin’s lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199)

Phillips, Darren C.; Xiao, Yu; Lam, Lloyd T.; Litvinovich, Elizabeth; Roberts-Rapp, Lisa; Souers, Andrew J.; Leverson, Joel D.

doi:10.1038/bcj.2015.88

Cited by 98 publications

(91 citation statements)

References 53 publications

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“…For instance, targeting additional antiapoptotic proteins known to cause resistance to venetoclax (eg, MCL1 or BCL-XL) may be required. 95,96 Targeting MYC may be helpful, but identifying specific inhibitors to MYC protein has been an ongoing challenge, as reviewed in McKeown and Bradner. 97 MYC has a shorter half-life than BCL2 (;4 vs ;24 hours), and inhibiting translation or transcription is effective in treating Em-Myc lymphomas.…”

Section: 89mentioning

confidence: 99%

Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements

Sesques

Johnson

2017

Blood

137

116

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High-grade B-cell lymphomas (HGBLs) with MYC and BCL2 and/or BCL6 rearrangements, so-called “double-hit” lymphomas (HGBL-DH), are aggressive lymphomas that form a separate provisional entity in the 2016 revised World Health Organization Classification of Lymphoid Tumors. Fluorescence in situ hybridization (FISH) will be required to identify HGBL-DH and will reclassify a subset of diffuse large B-cell lymphomas (DLBCLs) and HGBLs with features intermediate between DLBCL and Burkitt lymphoma into this new category. Identifying patients with HGBL-DH is important because it may change clinical management. This poses a challenge for centers that may not be ready to handle the additional workload and financial burden associated with the increase in requests for FISH testing. Herein, we review the mechanisms of deregulation of these oncogenes. We identify the factors associated with a poor prognosis and those that can guide diagnostic testing. Restricting FISH analysis to the 10% of DLBCL patients who have a germinal center B-cell phenotype and coexpress MYC and BCL2 proteins would be cost-effective and would identify the subset of patients who are at highest risk of experiencing a relapse following conventional therapy. These patients may benefit from intensified chemotherapy regimens or, ideally, should enroll in clinical trials investigating novel regimens.

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Section: 89mentioning

confidence: 99%

Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements

Sesques

Johnson

2017

Blood

137

116

View full text Add to dashboard Cite

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“…Certain t(14;18)-positive cell lines such as SU-DHL-4, although high BCL-2 expressers, have been demonstrated to be resistant to venetoclax due to MCL-1 expression. In these cases, adding a CDK9 inhibitor (alvocidib/flavopiridol) or a direct inhibitor of MCL-1 (A-1210477) to venetoclax leads to synergistic cell killing (65). Additional synergies may also exist with other pathways known to promote tumor cell survival, as has been reported using the dual PI3K/mTOR (mammalian target of rapamycin) inhibitor BEZ235 and venetoclax (66).…”

Section: Identifying Sensitive Tumor Types and Likely Respondersmentioning

confidence: 99%

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

Sampath²,

et al. 2017

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Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high priority goal for cancer therapy. After decades of effort, drug discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL-2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL-2 biology, were essential to the development of BH3 mimetics such as the BCL-2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL-2 biology and facilitated the clinical development of venetoclax.

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“…By inhibiting MCL-1, A-1210477 was shown to interact synergistically with the BCL-2/BCL-xL inhibitor ABT-263 (navitoclax) to kill a variety of cancer cell types (34)(35)(36). We found that the combination of A-1210477 and cobimetinib was synergistic as shown by a mechanism that involved disruption of the interaction of MCL-1 with the pro-apoptotic BH3-only proteins BIM and BAK by A-1210477, and by the ability of cobimetinib to suppress MCL-1 and induce BIM expression.…”

Section: Discussionmentioning

confidence: 99%

Mutant BRAF upregulates MCL-1 to confer apoptosis resistance that is reversed by MCL-1 antagonism and cobimetinib in colorectal cancer.

Kawakami

Huang

Pal

et al. 2017

JCO

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Oncogenic BRAF V600E mutations activate MAP kinase signaling and are associated with treatment resistance and poor prognosis in patients with colorectal cancer (CRC). In BRAF V600E mutant CRCs, treatment failure may be related to BRAF V600E -mediated apoptosis resistance that occurs by an as yet undefined mechanism. We found that BRAF V600E can upregulate antiapoptotic MCL-1 in a gene dose-dependent manner using CRC cell lines isogenic for BRAF. BRAF V600E -induced MCL-1 upregulation was confirmed by ectopic BRAF V600E expression that activated MEK/ERK signaling to phosphorylate (MCL-1 Thr163 ) and stabilize MCL-1. Upregulation of MCL-1 was mediated by MEK/ERK shown by the ability of ERK siRNA to suppress MCL-1. Stabilization of MCL-1 by phosphorylation was shown by a phosphorylationmimicking mutant and an unphosphorylated MCL-1 mutant that decreased or increased MCL-1 protein turnover, respectively. MEK/ERK inhibition by cobimetinib suppressed MCL-1 expression/phosphorylation and induced pro-apoptotic BIM to a greater extent than did vemurafenib in BRAF V600E cell lines. MCL-1 knockdown vs control shRNA significantly enhanced cobimetinib-induced apoptosis in vitro and in HT29 colon cancer xenografts. The small molecule MCL-1 inhibitor, A-1210477 also enhanced cobimetinib-induced apoptosis in vitro that was due to disruption of the interaction of MCL-1 with pro-apoptotic BAK and BIM. Knockdown of BIM attenuated BAX, but not BAK, activation by cobimetinib plus A-1210477. In summary, BRAF V600E -mediated MEK/ERK activation can upregulate MCL-1 by phosphorylation/ stabilization to confer apoptosis resistance that can be reversed by MCL-1 antagonism combined with cobimetinib, suggesting a novel therapeutic strategy against BRAF V600E mutant CRCs.

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Loss in MCL-1 function sensitizes non-Hodgkin’s lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199)

Cited by 98 publications

References 53 publications

Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements

Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

Mutant BRAF upregulates MCL-1 to confer apoptosis resistance that is reversed by MCL-1 antagonism and cobimetinib in colorectal cancer.

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