CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer

Shawn F Johnson; Cristina Cruz; Ann Katrin Greifenberg; Sofia Dust; Daniel G Stover; David Chi; Benjamin Primack; Shiliang Cao; Andrea J Bernhardy; Rhiannon Coulson; Jean-Bernard Lazaro; Bose Kochupurakkal; Heather Sun; Christine Unitt; Lisa A Moreau; Kristopher A Sarosiek; Maurizio Scaltriti; Dejan Juric; José Baselga; Andrea L Richardson; Scott J Rodig; Alan D D'Andrea; Judith Balmaña; Neil Johnson; Matthias Geyer; Violeta Serra; Elgene Lim; Geoffrey I Shapiro

doi:10.1016/j.celrep.2016.10.077

CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer

Cell Rep. 2016 Nov 22;17(9):2367-2381. doi: 10.1016/j.celrep.2016.10.077.

Authors

Shawn F Johnson¹, Cristina Cruz², Ann Katrin Greifenberg³, Sofia Dust³, Daniel G Stover⁴, David Chi¹, Benjamin Primack⁵, Shiliang Cao¹, Andrea J Bernhardy⁶, Rhiannon Coulson⁷, Jean-Bernard Lazaro⁸, Bose Kochupurakkal⁸, Heather Sun⁹, Christine Unitt⁹, Lisa A Moreau⁵, Kristopher A Sarosiek¹, Maurizio Scaltriti¹⁰, Dejan Juric¹¹, José Baselga¹⁰, Andrea L Richardson⁹, Scott J Rodig⁹, Alan D D'Andrea⁵, Judith Balmaña¹², Neil Johnson⁶, Matthias Geyer³, Violeta Serra¹³, Elgene Lim¹⁴, Geoffrey I Shapiro¹⁵

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ Developmental Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
⁷ The Kinghorn Cancer Centre, Garvan Institute of Medical Research, St. Vincent's Health Network, Darlinghurst, NSW 2010, Australia.
⁸ Department of Radiation Oncology and Center for DNA Damage and Repair, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
⁹ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
¹⁰ Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹¹ Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
¹² Medical Oncology Department, Hospital Vall d'Hebron, Vall d'Hebron Institute of Oncology, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain.
¹³ Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, 08035 Barcelona, Spain.
¹⁴ 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.
¹⁵ 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.

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.

Keywords: BRCA-associated breast cancer; CDK inhibitor; CDK12; PARP inhibitor; dinaciclib; homologous recombination repair; triple-negative breast cancer.

MeSH terms

Amino Acid Sequence
Animals
BRCA1 Protein / genetics
BRCA1 Protein / metabolism*
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Cell Line, Tumor
Cyclic N-Oxides
Cyclin-Dependent Kinases / antagonists & inhibitors*
Cyclin-Dependent Kinases / chemistry
Cyclin-Dependent Kinases / metabolism
DNA Damage / genetics
DNA Repair / drug effects
Drug Resistance, Neoplasm / drug effects*
Female
Gene Expression Regulation, Neoplastic / drug effects
Gene Knockout Techniques
Homologous Recombination / drug effects
Humans
Indolizines
Mice
Mutation / genetics*
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
Protein Kinase Inhibitors / pharmacology
Pyridinium Compounds / pharmacology
RNA, Small Interfering / metabolism
Transcription, Genetic / drug effects
Triple Negative Breast Neoplasms / enzymology*
Triple Negative Breast Neoplasms / genetics
Triple Negative Breast Neoplasms / pathology*
Xenograft Model Antitumor Assays

Substances

BRCA1 Protein
BRCA1 protein, human
Bridged Bicyclo Compounds, Heterocyclic
Cyclic N-Oxides
Indolizines
Poly(ADP-ribose) Polymerase Inhibitors
Protein Kinase Inhibitors
Pyridinium Compounds
RNA, Small Interfering
dinaciclib
CDK12 protein, human
Cyclin-Dependent Kinases

Abstract

MeSH terms

Substances

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