Journal
ONCOGENE
Volume 37, Issue 37, Pages 5066-5078Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41388-018-0332-y
Keywords
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Funding
- NIH/NCI Cancer Center Support Grant [P30 CA008748]
- NCI Soft Tissue Sarcoma SPORE [CA140146]
- Maloris Foundation
- Linn Fund from Cycle For Survival
- Heidi Connery Memorial Research Grant from the Sarcoma Foundation of America
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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.
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