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Oncogene. 2018 Sep;37(37):5066-5078. doi: 10.1038/s41388-018-0332-y. Epub 2018 May 23.

PDLIM7 and CDH18 regulate the turnover of MDM2 during CDK4/6 inhibitor therapy-induced senescence.

Author information

1
The Louis V. Gerstner Graduate School of Biomedical Science, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
2
The Programs in MolecularMemorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
3
Departments of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
4
Departments of Medicine, Weill Cornell Medical College, New York, NY, 10021, USA.
5
Departments of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
6
Departments of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
7
Center for Advanced Retinal and Ocular Therapeutics, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
8
Developmental Biology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
9
Division of Hematology and Oncology, Columbia University Medical Center, Herbert Irving Pavilion 9th floor, 161 Fort Washington Avenue, New York, NY, 10032, USA.
10
Departments of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
11
Departments of Surgery, Weill Cornell Medical College, New York, NY, 10021, USA.
12
The Louis V. Gerstner Graduate School of Biomedical Science, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. koffa@mskcc.org.
13
The Programs in MolecularMemorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. koffa@mskcc.org.

Abstract

CDK4/6 inhibitors are being used to treat a variety of human malignancies. In well-differentiated and dedifferentiated liposarcoma their clinical promise is associated with their ability to downregulate the MDM2 protein. The downregulation of MDM2 following treatment with CDK4/6 inhibitors also induces many cultured tumor cell lines derived from different types of malignancies to progress from quiescence into senescence. Here we used cultured human cell lines and defined a role for PDLIM7 and CDH18, regulating MDM2 protein in CDK4/6 inhibitor-treated cells. Materials from our previous phase II trials with palbociclib were then used to demonstrate that expression of CDH18 protein was associated with response, measured as both progression-free survival and overall survival. This supports the hypothesis that the biologic transition from quiescence to senescence has clinical relevance for this class of drugs.

PMID:
29789718
PMCID:
PMC6137027
DOI:
10.1038/s41388-018-0332-y
[Indexed for MEDLINE]
Free PMC Article

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