The splicing modulator sudemycin induces a specific antitumor response and cooperates with ibrutinib in chronic lymphocytic leukemia

Xargay-Torrent, Sílvia; López‐Guerra, Mònica; Rosich, Laia; Montraveta, Arnau; Roldán, Jocabed; Rodríguez, Vanina; Villamor, Neus; Aymerich, Marta; Lagisetti, Chandraiah; Webb, Thomas R.; López-Otı́n, Carlos; Campo, Elı́as; Colomer, Dolors

doi:10.18632/oncotarget.4212

Cited by 65 publications

(54 citation statements)

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“…Recent studies have suggested that cancers with spliceosome gene mutations may have an increased sensitivity to splicing modulator drugs like sudemycin;323334 this study provides further evidence to support this hypothesis. Specifically, we show that mutant U2AF1 cells are sensitive to in vivo treatment with sudemycin.…”

Section: Discussionsupporting

confidence: 70%

Mutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome

et al. 2017

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Somatic mutations in spliceosome genes are detectable in ∼50% of patients with myelodysplastic syndromes (MDS). We hypothesize that cells harbouring spliceosome gene mutations have increased sensitivity to pharmacological perturbation of the spliceosome. We focus on mutant U2AF1 and utilize sudemycin compounds that modulate pre-mRNA splicing. We find that haematopoietic cells expressing mutant U2AF1(S34F), including primary patient cells, have an increased sensitivity to in vitro sudemycin treatment relative to controls. In vivo sudemycin treatment of U2AF1(S34F) transgenic mice alters splicing and reverts haematopoietic progenitor cell expansion induced by mutant U2AF1 expression. The splicing effects of sudemycin and U2AF1(S34F) can be cumulative in cells exposed to both perturbations—drug and mutation—compared with cells exposed to either alone. These cumulative effects may result in downstream phenotypic consequences in sudemycin-treated mutant cells. Taken together, these data suggest a potential for treating haematological cancers harbouring U2AF1 mutations with pre-mRNA splicing modulators like sudemycins.

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Section: Discussionsupporting

confidence: 70%

Mutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome

et al. 2017

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“…88 Primary human MDS/AML cells with mutant U2AF1 had impaired proliferation after treatment with SD1 in vitro compared with cells lacking splicing factor mutations and in vivo treatment of mice with SD6 reverted aberrant hematopoietic progenitor expansion in an inducible mouse model of mutant U2AF1. 89 FD-895 caused induction of apoptosis in CLL cells in vitro (independent of SF3B1 genotype) at nanomolar concentrations, similar to PB.…”

Section: Splicing Modulatorsmentioning

confidence: 95%

Splicing factor gene mutations in hematologic malignancies

Sáez

Walter

Graubert

2017

Blood

112

108

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Alternative splicing generates a diversity of messenger RNA (mRNA) transcripts from a single mRNA precursor and contributes to the complexity of our proteome. Splicing is perturbed by a variety of mechanisms in cancer. Recurrent mutations in splicing factors have emerged as a hallmark of several hematologic malignancies. Splicing factor mutations tend to occur in the founding clone of myeloid cancers, and these mutations have recently been identified in blood cells from normal, healthy elderly individuals with clonal hematopoiesis who are at increased risk of subsequently developing a hematopoietic malignancy, suggesting that these mutations contribute to disease initiation. Splicing factor mutations change the pattern of splicing in primary patient and mouse hematopoietic cells and alter hematopoietic differentiation and maturation in animal models. Recent developments in this field are reviewed here, with an emphasis on the clinical consequences of splicing factor mutations, mechanistic insights from animal models, and implications for development of novel therapies targeting the precursor mRNA splicing pathway. (Blood. 2017;129(10):1260-1269 IntroductionThe control of messenger RNA (mRNA) processing is a crucial component of gene regulation. The precursor messenger RNA (premRNA) sequence contains exons that flank introns, which are removed during splicing.1 Human genes are remarkably complex, containing an average of 8 exons, with introns composing up to 90% of the pre-mRNA sequence.2,3 Up to 94% of human genes generate multiple mRNA isoforms. [4][5][6] The spliceosome is a multiprotein complex consisting of 5 small nuclear ribonucleoproteins (snRNPs) and more than 150 proteins that recognizes the elements near intron-exon boundaries and the branch site that catalyzes the excision of intronic regions. Additional trans-acting factors including SR proteins bind the cis-regulatory sequences (exonic and intronic silencers and enhancers) to promote or prevent spliceosome assembly. [7][8][9] The complexity of regulatory elements that control proper splicing makes this process not only critical to maintain tissue homeostasis, but also highly susceptible to hereditary and somatic mutations that are involved in disease. This review will discuss the implications of aberrant splicing on human disease, with a focus on the impact of somatic mutations in trans-acting splicing factors in hematologic malignancies. Splicing and diseaseA comprehensive analysis of The Cancer Genome Atlas (TCGA) project RNA sequencing (RNA-seq) data from 16 tumor types and matched normal tissue revealed evidence of global alternative splicing involving a variety of splicing junctions, including cassette exons, retrained introns, and competing 59 and 39 splice sites (SSs). 10 In particular, acute myeloid leukemia (AML) cells showed the largest number of alternative spliced events among tumor types.10 Recent evidence from analysis of paired DNA and RNA-seq data from TCGA has shown that somatic mutations affecting splicing regulatory sequences (sp...

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“…Further efforts are needed to determine whether this was an on- or off-target effect of U2 snRNP inhibition in vivo . In the meantime, several preclinical studies are evaluating the utility and safety of sudemycins 156,157 for cancer therapy.…”

Section: Implications For Therapymentioning

confidence: 99%

RNA splicing factors as oncoproteins and tumour suppressors

et al. 2016

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Preface The recent genomic characterization of cancers has revealed recurrent somatic point mutations and copy number changes affecting genes encoding RNA splicing factors. Initial studies of these ‘spliceosomal mutations’ suggest that the proteins bearing these mutations exhibit altered splice site and/or exon recognition preferences relative to their wild-type counterparts, resulting in cancer-specific mis-splicing. Such changes in the splicing machinery may create novel vulnerabilities in cancer cells that can be therapeutically exploited using compounds that can influence the splicing process. Further studies to dissect the biochemical, genomic, and biological effects of spliceosomal mutations are critical for the development of cancer therapies targeted to these mutations.

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The splicing modulator sudemycin induces a specific antitumor response and cooperates with ibrutinib in chronic lymphocytic leukemia

Cited by 65 publications

References 50 publications

Mutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome

Mutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome

Splicing factor gene mutations in hematologic malignancies

RNA splicing factors as oncoproteins and tumour suppressors

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