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PDLIM7 and CDH18 Regulate the Turnover of MDM2 During CDK4/6 Inhibitor Therapy-Induced Senescence

PDLIM7 and CDH18 Regulate the Turnover of MDM2 During CDK4/6 Inhibitor Therapy-Induced Senescence

Mary E Klein, Mark A Dickson, Cristina Antonescu, Li-Xuan Qin, Scott J Dooley, Afsar Barlas, Katia Manova, Gary K Schwartz, Aimee M Crago, Samuel Singer, Andrew Koff, William D Tap

Oncogene. 2018 Sep;37(37):5066-5078.

PMID: 29789718

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4248412	CDH18 human			Price

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