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...and induces lethality in mantle cell lymphoma | Oncogene

AbstractThe dysregulation of PI3K signaling has been implicated as an underlying mechanism associated with resistance to Bruton鈥檚 tyrosine kinase inhibition by ibrutinib in both chronic lymphocytic leukemia and mantle cell lymphoma (MCL). Ibrutinib resistance has become a major unmet clinical need, and the development of therapeutics to overcome ibrutinib resistance will greatly improve the poor outcomes of ibrutinib-exposed MCL patients. CUDC-907 inhibits both PI3K and HDAC functionality to exert synergistic or additive effects. Therefore, the activity of CUDC-907 was examined in MCL cell lines and patient primary cells, including ibrutinib-resistant MCL cells. The efficacy of CUDC-907 was further examined in an ibrutinib-resistant MCL patient-derived xenograft (PDX) mouse model. The molecular mechanisms by which CUDC-907 dually inhibits PI3K and histone deacetylation were assessed using reverse protein array, immunoblotting, and chromatin immunoprecipitation (ChIP) coupled with sequencing. We showed evidence that CUDC-907 treatment increased histone acetylation in MCL cells. We found that CUDC-907 caused decreased proliferation and increased apoptosis in MCL in vitro and in vivo MCL models. In addition, CUDC-907 was effective in inducing lethality in ibrutinib-resistant MCL cells. Lastly, CUDC-907 treatment increased histone acetylation in MCL cells. Overall, these studies suggest that CUDC-907 may be a promising therapeutic option for relapsed or resistant MCL. Subscribe to JournalGet full journal access for 1 year372,90 鈧?/p>only 7,46 鈧?per issueSubscribeAll prices are NET prices. VAT will be added later in the checkout.Tax calculation will be finalised during checkout.Rent or Buy articleGet time limited or full article access on ReadCube.from$8.99Rent or BuyAll prices are NET prices. All sequencing data will be deposited in the NCBI database of Genotypes and Phenotypes (dbGap, http://www.ncbi.nlm.nih.gov/gap). The data can be accessed under the accession number phs# (the submission process is currently ongoing, and the accession number is going to be updated once it is complete). References1.Cheah CY, Seymour JF, Wang ML. Mantle cell lymphoma. J Clin Oncol. 2016;34:1256鈥?9.CAS聽 Article聽Google Scholar聽 2.Dreyling M, Jurczak W, Jerkeman M, Silva RS, Rusconi C, Trneny M, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet. 2016;387:770鈥?.CAS聽 Article聽Google Scholar聽 3.Goy A. Mantle cell lymphoma: is it time for a new treatment paradigm? 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Cell line authentication was performed by the MD Anderson Cancer Center Characterized Cell Line Core Facility, funded by grant NCI # CA016672. Author contributions HG wrote the first draft of the manuscript; HG, KJN, EL, and MW wrote and revised the manuscript; HG, KJN, ZL, and MW conceived experiments; HG, DZ, HZ, TB, YL, YY, SH, CJL, EL, TG, CJ, MA, KJN, LZ, and MW carried out experiments and data analysis; JY performed bioinformatic analyses; SZ performed the statistical analysis. All authors have read and approved of the final manuscript. Author informationAffiliationsDepartment of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USAHui Guo,聽Dongfeng Zeng,聽Hui Zhang,聽Taylor Bell,聽Yang Liu,聽Shengjian Huang,聽Carrie J. Li,聽Elizabeth Lorence,聽Changying Jiang,聽Makhdum Ahmed,聽Yixin Yao,聽Krystle J. Nomie,聽Liang Zhang聽 聽Michael WangDepartment of Hematology, Xinqiao Hospital, The Third Military Medical University, 430000, Chongqing, ChinaDongfeng ZengDepartment of Molecular Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USAJun YaoDepartment of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USAShouhao ZhouInstitute of Hematology Oncology, The First Hospital of Harbin, 150010, Harbin, ChinaTiejun GongDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USAMichael WangAuthorsHui GuoView author publicationsYou can also search for this author in PubMed聽Google ScholarDongfeng ZengView author publicationsYou can also search for this author in PubMed聽Google ScholarHui ZhangView author publicationsYou can also search for this author in PubMed聽Google ScholarTaylor BellView author publicationsYou can also search for this author in PubMed聽Google ScholarJun YaoView author publicationsYou can also search for this author in PubMed聽Google ScholarYang LiuView author publicationsYou can also search for this author in PubMed聽Google ScholarShengjian HuangView author publicationsYou can also search for this author in PubMed聽Google ScholarCarrie J. LiView author publicationsYou can also search for this author in PubMed聽Google ScholarElizabeth LorenceView author publicationsYou can also search for this author in PubMed聽Google ScholarShouhao ZhouView author publicationsYou can also search for this author in PubMed聽Google ScholarTiejun GongView author publicationsYou can also search for this author in PubMed聽Google ScholarChangying JiangView author publicationsYou can also search for this author in PubMed聽Google ScholarMakhdum AhmedView author publicationsYou can also search for this author in PubMed聽Google ScholarYixin YaoView author publicationsYou can also search for this author in PubMed聽Google ScholarKrystle J. NomieView author publicationsYou can also search for this author in PubMed聽Google ScholarLiang ZhangView author publicationsYou can also search for this author in PubMed聽Google ScholarMichael WangView author publicationsYou can also search for this author in PubMed聽Google ScholarCorresponding authorCorrespondence to Michael Wang.Ethics declarations Conflict of interest The authors declare that they have no conflict of interest. Electronic supplementary material

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