Meayamycin inhibits pre–messenger RNA splicing and exhibits picomolar activity against multidrug-resistant cells

Albert, Brian J.; McPherson, Peter A.; O'Brien, Kristine; Czaicki, Nancy; DeStefino, Vincent; Osman, Sami; Li, Miaosheng; Day, Billy W.; Grabowski, Paula J.; Moore, Melissa J.; Vogt, Andreas; Koide, Kazunori

doi:10.1158/1535-7163.mct-09-0051

Cited by 93 publications

(113 citation statements)

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“…16,[26][27][28] Meayamycin has been found more potent and stable than its natural compound FR901464 in various tumor cell lines, including MCF-7 and MDA-MB231 breast cancer cell lines. 29 Sudemycins, analogs of parental compound FR901464, have also been developed to target SF3b and shown to modulate alternative splicing in human tumor xenografts. 28,30 E7107 entered clinical trials as an anticancer agent.…”

Section: Discussionmentioning

confidence: 99%

Expression levels of SF3B3 correlate with prognosis and endocrine resistance in estrogen receptor-positive breast cancer

et al. 2015

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De novo or acquired resistance to endocrine therapy limits its utility in a significant number of estrogen receptor-positive (ER-positive) breast cancers. It is crucial to identify novel targets for therapeutic intervention and improve the success of endocrine therapies. Splicing factor 3b, subunit 1 (SF3B1) mutations are described in luminal breast cancer albeit in low frequency. In this study, we evaluated the role of SF3B1 and SF3B3, critical parts of the SF3b splicing complex, in ER-positive endocrine resistance. To ascertain the role of SF3B1/SF3B3 in endocrine resistance, their expression levels were evaluated in ER-positive/endocrine-resistant cell lines (MCF-7/LCC2 and MCF-7/LCC9) using a real-time quantitative reverse transcription PCR (qRT-PCR). To further determine their clinical relevance, expression analysis was performed in a cohort of 60 paraffin-embedded ER-positive, node-negative breast carcinomas with low, intermediate, and high Oncotype DX recurrence scores. Expression levels of SF3B1 and SF3B3 and their prognostic value were validated in large cohorts using publicly available gene expression data sets including The Cancer Genome Atlas. SF3B1 and SF3B3 levels were significantly increased in ERa-positive cells with acquired tamoxifen (MCF-7/LCC2; both Po0.0002) and fulvestrant/tamoxifen resistance (MCF-7/LCC9; P ¼ 0.008 for SF3B1 and P ¼ 0.0006 for SF3B3). Expression levels of both MCF-7/LCC2 and MCF-7/LCC9 were not affected by additional treatments with E2 and/or tamoxifen. Furthermore, qRT-PCR analysis confirmed that SF3B3 expression is significantly upregulated in Oncotype DX high-risk groups when compared with low risk (P ¼ 0.019). Similarly, in publicly available breast cancer gene expression data sets, overexpression of SF3B3, but not SF3B1, was significantly correlated with overall survival. Furthermore, the correlation was significant in ER-positive, but not in ER-negative tumors.This is the first study to document the role of SF3B3 in endocrine resistance and prognosis in ER-positive breast cancer. Potential strategies for therapeutic targeting of the splicing mechanism(s) need to be evaluated. The process of alternative splicing results in synthesis of multiple mRNA variants from a single gene. Earlier studies reported the importance of splice variants in a number of key genes regulating signaling pathways such as apoptosis, metabolism, and angiogenesis. Alterations in expression of some splicing factors, genes that regulate splicing process of mature messenger RNA species from primary transcripts, have also been reported in various cancers including breast cancer. 1 The utilization of next-generation sequencing technologies have further revealed the presence of somatic mutations in splicing factors. 2 Among them, the SF3B1 mutations occurred in several types of hematological malignancies as well as in solid cancers, such as breast, pancreatic cancers, and uveal melanomas. [3][4][5][6][7] These mutations were shown to be

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Section: Discussionmentioning

confidence: 99%

Expression levels of SF3B3 correlate with prognosis and endocrine resistance in estrogen receptor-positive breast cancer

et al. 2015

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“…Structure-activity relationship (SAR) data for the three compounds and related molecules have been steadily emerging (Sakai et al 2002;Mizui et al 2004;Lagisetti et al 2008Lagisetti et al , 2013Lagisetti et al , 2014Albert et al 2009;Fan et al 2011;Gundluru et al 2011;Muller et al 2011;Villa et al 2012Villa et al , 2013Gao et al 2013;Ghosh and Chen 2013;Arai et al 2014;Effenberger et al 2014;Ghosh et al 2014a,b,c;He et al 2014). SSA (1), which is similar to FR901464 (Nakajima et al 1996b), meayamycin (Albert et al 2009), thailanstatins (Liu et al 2013), and sudemycins (Fan et al 2011), differs in structure relative to the other two compounds. PB (2), which is related to E7107 and FD-895 (Kotake et al 2007;Villa et al 2012), and HB (3), a member of GEX1 family (Sakai et al 2002), share a similar side chain, but have different ring structures (macrolide vs. tetrahydropyran).…”

Section: Introductionmentioning

confidence: 99%

Interchangeable SF3B1 inhibitors interfere with pre-mRNA splicing at multiple stages

Effenberger

Urabe

Prichard

et al. 2016

RNA

102

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The protein SF3B1 is a core component of the spliceosome, the large ribonucleoprotein complex responsible for pre-mRNA splicing. Interest in SF3B1 intensified when tumor exome sequencing revealed frequent specific SF3B1 mutations in a variety of neoplasia and when SF3B1 was identified as the target of three different cancer cell growth inhibitors. A better mechanistic understanding of SF3B1's role in splicing is required to capitalize on these discoveries. Using the inhibitor compounds, we probed SF3B1 function in the spliceosome in an in vitro splicing system. Formerly, the inhibitors were shown to block early steps of spliceosome assembly, consistent with a previously determined role of SF3B1 in intron recognition. We now report that SF3B1 inhibitors also interfere with later events in the spliceosome cycle, including exon ligation. These observations are consistent with a requirement for SF3B1 throughout the splicing process. Additional experiments aimed at understanding how three structurally distinct molecules produce nearly identical effects on splicing revealed that inactive analogs of each compound interchangeably compete with the active inhibitors to restore splicing. The competition indicates that all three types of compounds interact with the same site on SF3B1 and likely interfere with its function by the same mechanism, supporting a shared pharmacophore model. It also suggests that SF3B1 inhibition does not result from binding alone, but is consistent with a model in which the compounds affect a conformational change in the protein. Together, our studies reveal new mechanistic insight into SF3B1 as a principal player in the spliceosome and as a target of inhibitor compounds.

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“…9,12 Therefore targeting the spliceosome may be a novel therapeutic approach for the treatment of CLL. Several compounds are available for this purpose, [13][14][15][16] including meayamycin B 17,18 and the structurally related spliceostatin A (SSA). 16 SSA is a synthetically modified analog of the natural product FR901464, 19 while meayamycin B is prepared by total synthesis.…”

Section: Introductionmentioning

confidence: 99%

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

et al. 2015

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The pro-survival Bcl-2 family member Mcl-1 is expressed in chronic lymphocytic leukemia (CLL), with high expression correlated with progressive disease. The spliceosome inhibitor spliceostatin A (SSA), is known to regulate Mcl-1 and so here we assessed the ability of SSA to elicit apoptosis in CLL. SSA induced apoptosis of CLL cells at low nanomolar concentrations in a dose-and time-dependent manner, but independently of SF3B1 mutational status, IGHV status and CD38 or ZAP70 expression.However, normal B and T cells were less sensitive than CLL cells (p=0.006 and p<0.001, respectively).

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Meayamycin inhibits pre–messenger RNA splicing and exhibits picomolar activity against multidrug-resistant cells

Cited by 93 publications

References 48 publications

Expression levels of SF3B3 correlate with prognosis and endocrine resistance in estrogen receptor-positive breast cancer

Expression levels of SF3B3 correlate with prognosis and endocrine resistance in estrogen receptor-positive breast cancer

Interchangeable SF3B1 inhibitors interfere with pre-mRNA splicing at multiple stages

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

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