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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.
Highlights
The commitment to cell proliferation is initiated when extracellular signals converge at the cell cycle and induce the expression of D-type cyclins, their association withThese authors are co-communicating authors: Andrew Koff and William D
To gain insight into how MDM2 turnover was prevented in PD0332991-induced quiescent cells we carried out a smalltargeted knockdown screen where we attempted to individually reduce expression of CREBBP, NEDD4-1, PDLIM7, PRKCD, or p300, all previously reported to regulate MDM2 auto-ubiqutination [19]
MDM2 downregulation is necessary for CDK4/6 inhibitor therapy-induced senescence in a variety of cancer cell lines, and the loss of MDM2 is observed post palbociclib treatment in patients with WD/DDLS who have prolonged periods of progression-free survival (PFS) [18]
Summary
The commitment to cell proliferation is initiated when extracellular signals converge at the cell cycle and induce the expression of D-type cyclins, their association with. These authors are co-communicating authors: Andrew Koff and William D. The cyclin D-associated kinases are necessary for the proliferation of Rb-positive cells because they initiate the phosphorylation-dependent cascade that inactivates this tumor suppressor [2, 4]. Unchecked proliferation of Rb-positive tumor cells is commonly associated with mutations that dysregulate this pathway: including the overexpression of D-type cyclins, the mutation or overexpression of CDK4, or mutations in the INK4 family of CDK inhibitors [3, 5, 6]. The importance of cyclin D holoenzymes for inactivation of Rb and the development of cancer in mice prompted the development of CDK4/6
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