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 RichardsonScott J. Rodig, Alan D. D'Andrea, Judith Balmaña, Neil Johnson, Matthias Geyer, Violeta Serra, Elgene Lim, Geoffrey I. Shapiro

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2367-2381
Number of pages15
JournalCell Reports
Volume17
Issue number9
DOIs
StatePublished - Nov 22 2016

Fingerprint

Triple Negative Breast Neoplasms
Homologous Recombination
Poly(ADP-ribose) Polymerases
Heterografts
Cells
CDC2 Protein Kinase
Cyclin-Dependent Kinase 2
Restoration
Tumors
Poly(ADP-ribose) Polymerase Inhibitors
Neoplasms
dinaciclib
Cell Line
Growth

Keywords

  • BRCA-associated breast cancer
  • CDK inhibitor
  • CDK12
  • dinaciclib
  • homologous recombination repair
  • PARP inhibitor
  • triple-negative breast cancer

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer. / Johnson, Shawn F.; Cruz, Cristina; Greifenberg, Ann Katrin; Dust, Sofia; Stover, Daniel G.; Chi, David; Primack, Benjamin; Cao, Shiliang; Bernhardy, Andrea J.; Coulson, Rhiannon; Lazaro, Jean Bernard; Kochupurakkal, Bose; Sun, Heather; Unitt, Christine; Moreau, Lisa A.; Sarosiek, Kristopher A.; Scaltriti, Maurizio; Juric, Dejan; Baselga, José; Richardson, Andrea; Rodig, Scott J.; D'Andrea, Alan D.; Balmaña, Judith; Johnson, Neil; Geyer, Matthias; Serra, Violeta; Lim, Elgene; Shapiro, Geoffrey I.

In: Cell Reports, Vol. 17, No. 9, 22.11.2016, p. 2367-2381.

Research output: Contribution to journalArticle

Johnson, SF, Cruz, C, Greifenberg, AK, Dust, S, Stover, DG, Chi, D, Primack, B, Cao, S, Bernhardy, AJ, Coulson, R, Lazaro, JB, Kochupurakkal, B, Sun, H, Unitt, C, Moreau, LA, Sarosiek, KA, Scaltriti, M, Juric, D, Baselga, J, Richardson, A, Rodig, SJ, D'Andrea, AD, Balmaña, J, Johnson, N, Geyer, M, Serra, V, Lim, E & Shapiro, GI 2016, 'CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer', Cell Reports, vol. 17, no. 9, pp. 2367-2381. https://doi.org/10.1016/j.celrep.2016.10.077
Johnson, Shawn F. ; Cruz, Cristina ; Greifenberg, Ann Katrin ; Dust, Sofia ; Stover, Daniel G. ; Chi, David ; Primack, Benjamin ; Cao, Shiliang ; Bernhardy, Andrea J. ; Coulson, Rhiannon ; Lazaro, Jean Bernard ; Kochupurakkal, Bose ; Sun, Heather ; Unitt, Christine ; Moreau, Lisa A. ; Sarosiek, Kristopher A. ; Scaltriti, Maurizio ; Juric, Dejan ; Baselga, José ; Richardson, Andrea ; Rodig, Scott J. ; D'Andrea, Alan D. ; Balmaña, Judith ; Johnson, Neil ; Geyer, Matthias ; Serra, Violeta ; Lim, Elgene ; Shapiro, Geoffrey I. / CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer. In: Cell Reports. 2016 ; Vol. 17, No. 9. pp. 2367-2381.
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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 J.

AU - D'Andrea, Alan D.

AU - Balmaña, Judith

AU - Johnson, Neil

AU - Geyer, Matthias

AU - Serra, Violeta

AU - Lim, Elgene

AU - Shapiro, Geoffrey I.

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.

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