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

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

118 Scopus citations

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 language	English (US)
Pages (from-to)	2367-2381
Number of pages	15
Journal	Cell Reports
Volume	17
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2016.10.077
State	Published - Nov 22 2016

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2016.10.077

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Johnson, S. F., Cruz, C., Greifenberg, A. K., Dust, S., Stover, D. G., Chi, D., Primack, B., Cao, S., Bernhardy, A. J., Coulson, R., Lazaro, J. B., Kochupurakkal, B., Sun, H., Unitt, C., Moreau, L. A., Sarosiek, K. A., Scaltriti, M., Juric, D., Baselga, J., ... Shapiro, G. I. (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, 17(9), 2367-2381. https://doi.org/10.1016/j.celrep.2016.10.077

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, AL, 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

@article{920a12d6c6334551bc5680608e5cea22,

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.",

keywords = "BRCA-associated breast cancer, CDK inhibitor, CDK12, PARP inhibitor, dinaciclib, homologous recombination repair, triple-negative breast cancer",

author = "Johnson, {Shawn F.} and Cristina Cruz and Greifenberg, {Ann Katrin} and Sofia Dust and Stover, {Daniel G.} and David Chi and Benjamin Primack and Shiliang Cao and Bernhardy, {Andrea J.} and Rhiannon Coulson and Lazaro, {Jean Bernard} and Bose Kochupurakkal and Heather Sun and Christine Unitt and Moreau, {Lisa A.} and Sarosiek, {Kristopher A.} and Maurizio Scaltriti and Dejan Juric and Jos{\'e} Baselga and Richardson, {Andrea L.} and Rodig, {Scott J.} and D'Andrea, {Alan D.} and Judith Balma{\~n}a and Neil Johnson and Matthias Geyer and Violeta Serra and Elgene Lim and Shapiro, {Geoffrey I.}",

note = "Publisher Copyright: {\textcopyright} 2016 The Author(s)",

year = "2016",

month = nov,

day = "22",

doi = "10.1016/j.celrep.2016.10.077",

language = "English (US)",

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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 L.

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.

KW - BRCA-associated breast cancer

KW - CDK inhibitor

KW - CDK12

KW - PARP inhibitor

KW - dinaciclib

KW - homologous recombination repair

KW - triple-negative breast cancer

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DO - 10.1016/j.celrep.2016.10.077

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C2 - 27880910

AN - SCOPUS:84996656468

SN - 2211-1247

VL - 17

SP - 2367

EP - 2381

JO - Cell Reports

JF - Cell Reports

IS - 9

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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