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Synergistic anti-cancer activity of CDK4/6 inhibitor palbociclib and dual mTOR kinase inhibitor MLN0128 in pRb-expressing ER-negative breast cancer

  • Preclinical study
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Abstract

Purpose

Palbociclib is an approved cyclin-dependent kinase (CDK) 4/6 inhibitor for treatment of patients with ER-positive and HER2-negative breast cancers. While Retinoblastoma protein (pRb), a major substrate of CDK4/6, is a potential target in triple negative breast cancer (TNBC), the usefulness of CDK4/6 inhibitors in this cancer has not been established. This preclinical study investigated the combination effects of palbociclib and the dual mammalian target of rapamycin (mTOR) kinase inhibitor MLN0128 in estrogen receptor (ER)-negative breast cancer in vitro and in vivo.

Methods

The combined effects of two drugs on three TNBC cell lines (MB231, MB468, and CAL148) and an ER-negative and HER2-positive cell line (MB453) were investigated by MTT assay and colony formation analysis. Cell cycle measurements were examined as well as changes in expression of molecules related to G1/S transition and the mTOR pathway. Importantly, a pRb-expressing TNBC patient-derived xenograft (PDX) model was used to assess the effects of the combination in vivo.

Results

A combination of palbociclib and MLN0128 synergistically inhibited the proliferation of pRb-expressing cell lines and induced G1 cell cycle arrest. Western blot analysis revealed that CDK4/6-pRb and mTOR pathways were inhibited by these treatments. In pRb-expressing TNBC PDX, the combination treatment drastically suppressed tumor growth compared to either the control or single drug treatments. In addition, the combination treatment significantly reduced the number of Ki67-positive cells.

Conclusions

We revealed that palbociclib and MLN0128 had synergistic anti-cancer activity in both pRb + ER-negative cell lines and a TNBC PDX model. Our results indicate that such combination therapy is worthy of further investigation in a clinical setting.

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Abbreviations

CDK:

Cyclin-dependent kinase

DMSO:

Dimethyl sulfoxide

EMT:

Epithelialmesenchymal transition

FBS:

Fetal bovine serum

IHC:

Immunohistochemistry

mTOR:

The mammalian target of rapamycin

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NSG:

NOD-scid/IL2Rγ−/−

PBS:

Phosphate-buffered saline

PDX:

Patient-derived xenograft

PI3K:

Phosphatidylinositol 3-kinase

pRb:

Retinoblastoma protein

TNBC:

Triple negative breast cancer

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Acknowledgements

Research reported in this publication included works performed in the Analytical Cytometry Core, Pathology Research Services Pathology Core, and Animal Resource Center supported by the NCI (P30CA033572). We also want to thank the patient who donated her tumor tissue for us to generate the PDX, COH_GS6. In addition, we would like to thank Ian Talisman, PhD for editing the manuscript.

Funding

This work was supported by the Panda Charitable Foundation and the National Cancer Institute (P30CA033572) for the use of Analytical Cytometry Core, Pathology Research Services Pathology Core, and Animal Resource Center. SC is the Lester M. and Irene C. Finkelstein Chair in Biology.

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  1. Department of Cancer Biology, Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA

    Takuro Yamamoto, Noriko Kanaya & Shiuan Chen

  2. Department of Medical Oncology, City of Hope Medical Center, Duarte, CA, 91010, USA

    George Somlo

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  1. Takuro Yamamoto
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Correspondence to Shiuan Chen.

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All animal research procedures in this study were approved by the Institutional Animal Care and Use Committee at City of Hope. Facilities are credited by Association for Assessment and Accreditation of Laboratory Animal Care and operated according to NIH guidelines. This study was approved by the City of Hope Institutional Review board

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Informed consent was obtained from all individual patients prior to tissue collection.

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Yamamoto, T., Kanaya, N., Somlo, G. et al. Synergistic anti-cancer activity of CDK4/6 inhibitor palbociclib and dual mTOR kinase inhibitor MLN0128 in pRb-expressing ER-negative breast cancer. Breast Cancer Res Treat 174, 615–625 (2019). https://doi.org/10.1007/s10549-018-05104-9

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