CDK12 inhibition reverses de novo and acquired PARP inhibitor resistance in BRCA Wild-Type and mutated models of Triple-Negative breast Cancer
Open accessAbstract
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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Inhibiting CDK12 can sensitize cancer cells to PARP inhibitors.
“Several studies have shown that inhibiting CDK12 can sensitize cancer cells to PARP inhibitors (Bajrami et al., 2014; Iniguez et al., 2018; Johnson et al., 2016).”
From Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation (2020) · cites this paper as Johnson et al., 2016
CDK12 inactivation causes reduced POLII elongation and premature polyadenylation of select genes enriched in the DNA damage response pathway, resulting in a BRCAness phenotype.
“CDK12 inactivation is known to cause reduced POLII elongation and premature polyadenylation of select genes enriched in the DNA damage response pathway, resulting in a BRCAness phenotype (Blazek et al., 2011; Dubbury et al., 2018; Johnson et al., 2016).”
From Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation (2020) · cites this paper as Johnson et al., 2016
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References 31 · Cited by 291
- Authors
- 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., Richardson, A. L., Rodig, S. J., D’Andrea, A. D., Balmaña, J., Johnson, N., Geyer, M., Serra, V., Lim, E., & Shapiro, G. I.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Universitat Autònoma de Barcelona (ES)
- University of Bonn (DE)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Fox Chase Cancer Center (US)
- Garvan Institute of Medical Research (AU)
- Memorial Sloan Kettering Cancer Center (US)
- Vall d'Hebron Institute of Oncology (ES)
- Corresponding author
- Lim, Elgene
- Shapiro, Geoffrey I.
- ORCID
- Johnson, Shawn F.
- Cruz, Cristina
- Stover, Daniel G.
- Chi, David
- Cao, Shiliang
- Coulson, Rhiannon
- Lazaro, Jean-Bernard
- Kochupurakkal, Bose
- Moreau, Lisa A.
- Sarosiek, Kristopher A.
- Scaltriti, Maurizio
- Juric, Dejan
- Richardson, Andrea L.
- Rodig, Scott J.
- D’Andrea, Alan D.
- Johnson, Neil
- Geyer, Matthias
- Serra, Violeta
- Lim, Elgene
- Shapiro, Geoffrey I.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-11
- Volume
- 17
- Issue
- 9
- Pages
- 2367-2381
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5176643
- OpenAlex
- W2556688586
- Cited by
- 291
- References
- 31
- Citations by year
- 2026: 25 · 2025: 18 · 2024: 32 · 2023: 30 · 2022: 33 · 2021: 38 · 2020: 43 · 2019: 29 · 2018: 22 · 2017: 21
- FWCI
- 12.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- NIH (R01 CA090687)
- Research Supplement to Promote Diversity in Health-Related Research
- Dana-Farber Specialized Program of Research Excellence (SPORE) in Breast Cancer (P50 CA168504)
- SPORE Diversity Career Development Award
- Susan G. Komen Investigator Initiated Research (IIR12223953)
- Dana-Farber Claudia Adams Barr Award
- National Health and Medical Research Council of Australia Fellowship
- Instituto de Salud Carlos III (PI12/02606)
- Asociación Española Contra el Cancer
- Deutsche Forschungsgemeinschaft (GE 976/9-1)
- Topics
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- dinaciclib, PARP inhibitor resistance, triple-negative breast cancer, BRCA1 mutation, BRCA2 mutation, homologous recombination deficiency, de novo resistance, acquired resistance, patient-derived xenografts, combination therapy
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Amino Acid Sequence, Animals, Cyclic N-Oxides, DNA Damage, DNA Repair, Female, Humans, Indolizines, Mutation, Pyridinium Compounds, Transcription, Genetic, Gene Expression Regulation, Neoplastic, Cyclin-Dependent Kinases, Drug Resistance, Neoplasm, Bridged Bicyclo Compounds, Heterocyclic, BRCA1 Protein, Xenograft Model Antitumor Assays, RNA, Small Interfering, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, Gene Knockout Techniques, Homologous Recombination, Triple Negative Breast Neoplasms
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