TY - JOUR
T1 - CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer
AU - Johnson, Shawn F.
AU - Cruz, Cristina
AU - Greifenberg, Ann Katrin
AU - Dust, Sofia
AU - Stover, Daniel G.
AU - Chi, David
AU - Primack, Benjamin
AU - Cao, Shiliang
AU - Bernhardy, Andrea J.
AU - Coulson, Rhiannon
AU - Lazaro, Jean Bernard
AU - Kochupurakkal, Bose
AU - Sun, Heather
AU - Unitt, Christine
AU - Moreau, Lisa A.
AU - Sarosiek, Kristopher A.
AU - Scaltriti, Maurizio
AU - Juric, Dejan
AU - Baselga, José
AU - Richardson, Andrea
AU - Rodig, Scott
AU - D'Andrea, Alan D.
AU - Balma, Judith Nã
AU - Johnson, Neil
AU - Geyer, Matthias
AU - Serra, Violeta
AU - Lim, Elgene
AU - Shapiro, Geoffrey I.
N1 - Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2016/11/22
Y1 - 2016/11/22
N2 - 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.
AB - 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.
KW - Amino Acid Sequence
KW - Animals
KW - BRCA1 Protein/genetics
KW - Bridged Bicyclo Compounds, Heterocyclic/pharmacology
KW - Cell Line, Tumor
KW - Cyclic N-Oxides
KW - Cyclin-Dependent Kinases/antagonists & inhibitors
KW - DNA Damage/genetics
KW - DNA Repair/drug effects
KW - Drug Resistance, Neoplasm/drug effects
KW - Female
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Gene Knockout Techniques
KW - Homologous Recombination/drug effects
KW - Humans
KW - Indolizines
KW - Mice
KW - Mutation/genetics
KW - Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
KW - Protein Kinase Inhibitors/pharmacology
KW - Pyridinium Compounds/pharmacology
KW - RNA, Small Interfering/metabolism
KW - Transcription, Genetic/drug effects
KW - Triple Negative Breast Neoplasms/enzymology
KW - Xenograft Model Antitumor Assays
UR - http://www.scopus.com/inward/record.url?scp=84996656468&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2016.10.077
DO - 10.1016/j.celrep.2016.10.077
M3 - Article
C2 - 27880910
SN - 2211-1247
VL - 17
SP - 2367
EP - 2381
JO - Cell Reports
JF - Cell Reports
IS - 9
ER -