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Novel combination treatment of CDK 4/6 inhibitors with PARP inhibitors in triple negative breast cancer cells

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Abstract

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors provide promising results for treating hormone receptor-positive breast cancer. However, the efficacy of CDK4/6 inhibitors remains uncertain in triple negative breast cancer (TNBC) patients with particularly carrying RB-deficient tumors. Poly-(ADP-ribose) polymerase (PARP) inhibitors offer a therapeutic strategy for the treatment of BRCA-mutated TNBC patients. However, the acquired drug resistance, changes in the cell cycle regulation, and DNA damage repair have demonstrated the necessity for developing new combination strategies. This preclinical study assessed a combinatory treatment of the CDK4/6 inhibitor abemaciclib with PARP inhibitors talazoparib (TAL) in HCC1937 BRCA-mutated RB-deficient TNBC cells and TAL-resistant HCC1937-R cells through WST-1 analysis, annexin V, cell cycle, acridine orange/propidium iodide staining, RT-PCR, and apoptosis array. Our findings revealed that abemaciclib and TAL combination synergistically suppressed the growth of TNBC cells and overcame TAL resistance through G0/G1 arrest and the activity of both intrinsic and extrinsic apoptotic pathways. These preliminary results suggest that the combination of abemaciclib and TAL could expand the use of these inhibitors in BRCA mutated and RB deficient TNBC patients and potentially overcomes PARP inhibitors resistance.

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Authors and Affiliations

  1. Department of Medical Biology, Faculty of Medicine, Sakarya University, Korucuk Campus, Sakarya, Turkey

    Gamze Guney Eskiler

  2. Department of Medical Biochemistry, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey

    Zeynep Ozman

  3. Department of Medical Biology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey

    Ayten Haciefendi

  4. Biotechnology Institute, Ankara University, Ankara, Turkey

    Demet Cansaran-Duman

Authors
  1. Gamze Guney Eskiler
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  2. Zeynep Ozman
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  3. Ayten Haciefendi
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  4. Demet Cansaran-Duman
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Contributions

GGE and ZO conceived and designed research. ZO and AH conducted experiments. GGE and DCD analyzed data and wrote the manuscript. All authors read and approved the manuscript.

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Correspondence to Gamze Guney Eskiler.

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Guney Eskiler, G., Ozman, Z., Haciefendi, A. et al. Novel combination treatment of CDK 4/6 inhibitors with PARP inhibitors in triple negative breast cancer cells. Naunyn-Schmiedeberg's Arch Pharmacol 396, 1031–1041 (2023). https://doi.org/10.1007/s00210-022-02375-4

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