title: Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells.
abstract: The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Although the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reverse Phase Protein Array and mass cytometry 'CyTOF' analyses demonstrated that ARV-825 caused greater perturbations in messenger RNA (mRNA) and protein expressions than OTX015 in sAML cells. Specifically, compared with OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, p-STAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared with OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against established and PD CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the in vitro generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the in vivo testing of the BRD4-PROTAC based combinations against post-MPN sAML.
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: D T
authors.initials: DT
authors.lastname: Saenz
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: W
authors.initials: W
authors.lastname: Fiskus
authors.affiliation: Arvinas LLC, New Haven, CT, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: T
authors.initials: T
authors.lastname: Manshouri
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: K
authors.initials: K
authors.lastname: Rajapakshe
authors.affiliation: Arvinas LLC, New Haven, CT, USA.
authors.forename: K
authors.initials: K
authors.lastname: Raina
authors.affiliation: Arvinas LLC, New Haven, CT, USA.
authors.forename: K G
authors.initials: KG
authors.lastname: Coleman
authors.affiliation: Arvinas LLC, New Haven, CT, USA.
authors.forename: A P
authors.initials: AP
authors.lastname: Crew
authors.affiliation: Arvinas LLC, New Haven, CT, USA.
authors.forename: A
authors.initials: A
authors.lastname: Shen
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Mill
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Biomedical Engineering, Georgia Tech and Emory University, Atlanta, GA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Qiu
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Kadia
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Pemmaraju
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: DiNardo
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: M-S
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Nowak
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Coarfa
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.|Department of Chemistry, Yale University, New Haven, CT, USA.|Department of Pharmacology, Yale University, New Haven, CT, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Crews
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Verstovsek
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: K N
authors.initials: KN
authors.lastname: Bhalla
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D018952:Antigens, CD34; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology / Q000627:therapeutic use; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D007938:Leukemia; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology; D009196:Myeloproliferative Disorders / Q000473:pathology; D009570:Nitriles; D009687:Nuclear Proteins / Q000378:metabolism; D059748:Proteolysis; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D014157:Transcription Factors / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D018952:Antigens, CD34; D001381:Azepines; D018797:Cell Cycle Proteins; D009570:Nitriles; D009687:Nuclear Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D013792:Thalidomide; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; C000606252:ARV-825; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C540383:ruxolitinib