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Research Watch

CDK12/13 Inhibitor SR-4835 Is Active in Triple-Negative Breast Cancer

DOI: 10.1158/2159-8290.CD-RW2019-164 Published December 2019
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  • Major Finding: The novel CDK12/13 inhibitor SR-4835 was effective in mouse models of triple-negative breast cancer.

  • Concept: SR-4835 is highly selective for CDK12/13 and synergizes with DNA-damaging agents.

  • Impact: Continued investigation of SR-4835 in triple-negative breast cancer is warranted.


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Some triple-negative breast cancers (TNBC) with mutations affecting homologous recombination, such as mutations in BRCA1, are sensitive to treatment with poly (ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapies; however, relapse is common with advanced disease. Quereda and colleagues report the development of the orally bioavailable CDK12/13 inhibitor SR-4835, an agent that may have potential for treatment of TNBC. The compound was developed using structure-guided optimization based on the most selective known inhibitor of CDK12/13, and biochemical assays using a panel of more than 450 kinases demonstrated that SR-4835 is highly selective for CDK12/13, with a half-maximal effective concentration of 100 nM. Further, TNBC cell lines exhibited sensitivity to low-nanomolar concentrations of the drug, and treatment resulted in an increase in DNA damage and apoptosis. Genetic inactivation of CDK12 or CDK13 resulted in a similar phenotype. RNA-sequencing experiments using cells treated with SR-4835 demonstrated that the drug caused downregulation of genes involved in DNA repair and recombination and upregulation of genes involved in cell-cycle progression and apoptosis. Accordingly, SR-4835 synergized with DNA-damaging agents and PARP inhibitors to inhibit cancer cell growth. Experiments using a patient-derived xenograft (PDX) model of TNBC showed that treatment with cisplatin or SR-4835 decreased tumor growth, and combination treatment with SR-4835 and cisplatin resulted in rapid tumor regression without apparent gross toxicity. In a second PDX model, similar results were observed following combination treatment with SR-4835 and irinotecan. Collectively, these findings suggest that SR-4835 is a promising early-stage drug worthy of further investigation in TNBC.

Quereda V, Bayle S, Vena F, Frydman SM, Monastyrskyi A, Roush WR, et al. Therapeutic targeting of CDK12/CDK13 in triple-negative breast cancer. Cancer Cell 2019;36:461–3.

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Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.

  • ©2019 American Association for Cancer Research.
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Cancer Discovery: 9 (12)
December 2019
Volume 9, Issue 12
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CDK12/13 Inhibitor SR-4835 Is Active in Triple-Negative Breast Cancer
Cancer Discov December 1 2019 (9) (12) 1644; DOI: 10.1158/2159-8290.CD-RW2019-164

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CDK12/13 Inhibitor SR-4835 Is Active in Triple-Negative Breast Cancer
Cancer Discov December 1 2019 (9) (12) 1644; DOI: 10.1158/2159-8290.CD-RW2019-164
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