{"title":"Abstract IA005: Therapeutic vulnerabilities of cohesin-mutant myeloid malignancies","authors":"Zuzana Tothova","doi":"10.1158/1538-8514.synthleth24-ia005","DOIUrl":null,"url":null,"abstract":"\n Splicing modulation is a promising treatment strategy pursued to date only in splicing-factor mutant cancers; however, its therapeutic potential is poorly understood outside of this context. Like splicing factors, genes encoding components of the cohesin complex are frequently mutated in myeloid malignancies, including 15-20% of myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (AML), where they are associated with poor outcomes. I will discuss our recent findings identifying cohesin mutations as biomarkers of sensitivity to drugs targeting splicing-factor SF3B1 (H3B-8800 and E-7107) and describe the mechanism by which drug-induced alterations in splicing of DNA repair genes, such as BRCA1 and BRCA2, underlie this sensitivity. We have demonstrated that treatment of cohesin-mutant cells with SF3B1 modulators results in impaired DNA damage response, accumulation of DNA damage, and increased sensitivity to PARP inhibitors and a panel of chemotherapeutic agents in vitro and in vivo, using AML cell lines and patient-derived xenograft models. Furthermore, we identified RAD51 foci formation as a predictive biomarker of sensitivity to SF3B1 splicing modulation alone or followed by sequential treatment with PARP inhibition and chemotherapy, and have identified additional non-cohesin mutant subtypes of MDS/AML and ovarian and breast cancer which are sensitive to this therapeutic approach. Our findings expand the potential therapeutic benefits of SF3B1 splicing modulators to include cohesin-mutant MDS/AML and we propose this as broader strategy for therapeutic targeting of other DNA damage-repair deficient cancers.\n Citation Format: Zuzana Tothova. Therapeutic vulnerabilities of cohesin-mutant myeloid malignancies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA005.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.3000,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Cancer Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1538-8514.synthleth24-ia005","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Splicing modulation is a promising treatment strategy pursued to date only in splicing-factor mutant cancers; however, its therapeutic potential is poorly understood outside of this context. Like splicing factors, genes encoding components of the cohesin complex are frequently mutated in myeloid malignancies, including 15-20% of myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (AML), where they are associated with poor outcomes. I will discuss our recent findings identifying cohesin mutations as biomarkers of sensitivity to drugs targeting splicing-factor SF3B1 (H3B-8800 and E-7107) and describe the mechanism by which drug-induced alterations in splicing of DNA repair genes, such as BRCA1 and BRCA2, underlie this sensitivity. We have demonstrated that treatment of cohesin-mutant cells with SF3B1 modulators results in impaired DNA damage response, accumulation of DNA damage, and increased sensitivity to PARP inhibitors and a panel of chemotherapeutic agents in vitro and in vivo, using AML cell lines and patient-derived xenograft models. Furthermore, we identified RAD51 foci formation as a predictive biomarker of sensitivity to SF3B1 splicing modulation alone or followed by sequential treatment with PARP inhibition and chemotherapy, and have identified additional non-cohesin mutant subtypes of MDS/AML and ovarian and breast cancer which are sensitive to this therapeutic approach. Our findings expand the potential therapeutic benefits of SF3B1 splicing modulators to include cohesin-mutant MDS/AML and we propose this as broader strategy for therapeutic targeting of other DNA damage-repair deficient cancers.
Citation Format: Zuzana Tothova. Therapeutic vulnerabilities of cohesin-mutant myeloid malignancies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA005.
期刊介绍:
Molecular Cancer Therapeutics will focus on basic research that has implications for cancer therapeutics in the following areas: Experimental Cancer Therapeutics, Identification of Molecular Targets, Targets for Chemoprevention, New Models, Cancer Chemistry and Drug Discovery, Molecular and Cellular Pharmacology, Molecular Classification of Tumors, and Bioinformatics and Computational Molecular Biology. The journal provides a publication forum for these emerging disciplines that is focused specifically on cancer research. Papers are stringently reviewed and only those that report results of novel, timely, and significant research and meet high standards of scientific merit will be accepted for publication.