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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

  • Takuro Yamamoto
  • Noriko Kanaya
  • George Somlo
  • Shiuan ChenEmail author
Preclinical study
  • 118 Downloads

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.

Keywords

Triple negative breast cancer (TNBC) CDK 4/6 inhibitor mTOR inhibitor Palbociclib MLN0128 Retinoblastoma protein (pRb) 

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

Notes

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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

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

Informed consent

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

Supplementary material

10549_2018_5104_MOESM1_ESM.pdf (187 kb)
Supplementary material 1 (PDF 187 KB) Supprementary Table S1. MLN0128 clinical trials for patients with breast cancer
10549_2018_5104_MOESM2_ESM.pdf (82 kb)
Supplementary material 2 (PDF 81 KB)

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Authors and Affiliations

  1. 1.Department of Cancer BiologyBeckman Research Institute of City of HopeDuarteUSA
  2. 2.Department of Medical OncologyCity of Hope Medical CenterDuarteUSA

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