title: CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer.
abstract: Although poly(ADP-ribose) polymerase (PARP) inhibitors are active in homologous recombination (HR)-deficient cancers, their utility is limited by acquired resistance after restoration of HR. Here, we report that dinaciclib, an inhibitor of cyclin-dependent kinases (CDKs) 1, 2, 5, and 9, additionally has potent activity against CDK12, a transcriptional regulator of HR. In BRCA-mutated triple-negative breast cancer (TNBC) cells and patient-derived xenografts (PDXs), dinaciclib ablates restored HR and reverses PARP inhibitor resistance. Additionally, we show that de novo resistance to PARP inhibition in BRCA1-mutated cell lines and a PDX derived from a PARP-inhibitor-naive BRCA1 carrier is mediated by residual HR and is reversed by CDK12 inhibition. Finally, dinaciclib augments the degree of response in a PARP-inhibitor-sensitive model, converting tumor growth inhibition to durable regression. These results highlight the significance of HR disruption as a therapeutic strategy and support the broad use of combined CDK12 and PARP inhibition in TNBC.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Shawn F
authors.initials: SF
authors.lastname: Johnson
authors.affiliation: Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, 08035 Barcelona, Spain; Medical Oncology Department, Hospital Vall d'Hebron, Vall d'Hebron Institute of Oncology, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cruz
authors.affiliation: Department of Structural Immunology, Institute of Innate Immunity, University of Bonn, 53127 Bonn, Germany; Group Physical Biochemistry, Center of Advanced European Studies and Research, 53175 Bonn, Germany.
authors.forename: Ann Katrin
authors.initials: AK
authors.lastname: Greifenberg
authors.affiliation: Department of Structural Immunology, Institute of Innate Immunity, University of Bonn, 53127 Bonn, Germany; Group Physical Biochemistry, Center of Advanced European Studies and Research, 53175 Bonn, Germany.
authors.forename: Sofia
authors.initials: S
authors.lastname: Dust
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Stover
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: David
authors.initials: D
authors.lastname: Chi
authors.affiliation: Department of Radiation Oncology and Center for DNA Damage and Repair, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children's Hospital and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Primack
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Shiliang
authors.initials: S
authors.lastname: Cao
authors.affiliation: Developmental Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Bernhardy
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, St. Vincent's Health Network, Darlinghurst, NSW 2010, Australia.
authors.forename: Rhiannon
authors.initials: R
authors.lastname: Coulson
authors.affiliation: Department of Radiation Oncology and Center for DNA Damage and Repair, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Lazaro
authors.affiliation: Department of Radiation Oncology and Center for DNA Damage and Repair, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Bose
authors.initials: B
authors.lastname: Kochupurakkal
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Unitt
authors.affiliation: Department of Radiation Oncology and Center for DNA Damage and Repair, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children's Hospital and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Moreau
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Kristopher A
authors.initials: KA
authors.lastname: Sarosiek
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Dejan
authors.initials: D
authors.lastname: Juric
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.affiliation: Department of Radiation Oncology and Center for DNA Damage and Repair, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children's Hospital and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Alan D
authors.initials: AD
authors.lastname: D'Andrea
authors.affiliation: Medical Oncology Department, Hospital Vall d'Hebron, Vall d'Hebron Institute of Oncology, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain.
authors.forename: Judith
authors.initials: J
authors.lastname: Balmaña
authors.affiliation: Developmental Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Johnson
authors.affiliation: Department of Structural Immunology, Institute of Innate Immunity, University of Bonn, 53127 Bonn, Germany; Group Physical Biochemistry, Center of Advanced European Studies and Research, 53175 Bonn, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Geyer
authors.affiliation: Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, 08035 Barcelona, Spain.
authors.forename: Violeta
authors.initials: V
authors.lastname: Serra
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Kinghorn Cancer Centre, Garvan Institute of Medical Research, St. Vincent's Health Network, Darlinghurst, NSW 2010, Australia. Electronic address: e.lim@garvan.org.au.
authors.forename: Elgene
authors.initials: E
authors.lastname: Lim
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: geoffrey_shapiro@dfci.harvard.edu.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D045744:Cell Line, Tumor; D003497:Cyclic N-Oxides; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055786:Gene Knockout Techniques; D059765:Homologous Recombination / Q000187:drug effects; D006801:Humans; D007212:Indolizines; D051379:Mice; D009154:Mutation / Q000235:genetics*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D007212:Indolizines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D047428:Protein Kinase Inhibitors; D011726:Pyridinium Compounds; D034741:RNA, Small Interfering; C553669:dinaciclib; C447339:CDK12 protein, human; D018844:Cyclin-Dependent Kinases
keywords: BRCA-associated breast cancer; CDK inhibitor; CDK12; PARP inhibitor; dinaciclib; homologous recombination repair; triple-negative breast cancer