CDK4 phosphorylation status and rational use for combining CDK4/6 and BRAF/MEK inhibition in advanced thyroid carcinomas.

Background: CDK4/6 inhibitors (CDK4/6i) have been established as standard treatment against advanced Estrogen Receptor-positive breast cancers. These drugs are being tested against several cancers, including in combinations with other therapies. We identified the T172-phosphorylation of CDK4 as the step determining its activity, retinoblastoma protein (RB) inactivation, cell cycle commitment and sensitivity to CDK4/6i.

Anaplastic thyroid carcinoma: advances in molecular profiling and targeted therapy.

Purpose Of Review: Anaplastic thyroid carcinomas (ATCs) are rare cancers with a globally very poor prognosis, because of their immensely aggressive behaviour, resulting in predominantly advanced stage of disease at diagnosis. Response to available therapies is still disappointing. Aim of the present review is to illustrate the diverse new strategies under investigation, to improve the poor outcome of these patients.

Monoclonal antibodies to activated CDK4: use to investigate normal and cancerous cell cycle regulation and involvement of phosphorylations of p21 and p27.

Cyclin-dependent kinase 4 (CDK4) is a master integrator that couples mitogenic/oncogenic signaling with the cell division cycle. It is deregulated in most cancers and inhibitors of CDK4 have become standard of care drugs for metastatic estrogen-receptor positive breast cancers and are being evaluated in a variety of other cancers. We previously characterized the T-loop phosphorylation at T172 of CDK4 as the highly regulated step that determines the activity of cyclin D-CDK4 complexes.

CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib.

Cyclin D-CDK4/6 are the first CDK complexes to be activated in the G1 phase in response to oncogenic pathways. The specific CDK4/6 inhibitor PD0332991 (palbociclib) was recently approved by the FDA and EMA for treatment of advanced ER-positive breast tumors. Unfortunately, no reliable predictive tools are available for identifying potentially responsive or insensitive tumors.

MiRNA expression may account for chronic but not for acute regulation of mRNA expression in human thyroid tumor models.

Background: For thyroid tumorigenesis, two main human in vitro models are available: primary cultures of human thyrocytes treated with TSH or EGF/serum as models for autonomous adenomas (AA) or papillary thyroid carcinomas (PTC) respectively, and human thyroid tumor derived cell lines. Previous works of our group have assessed properties of those models, with a special emphasis on mRNA regulations. It is often assumed that miRNA may be one of the primary events inducing these mRNA regulations.

Cell cycle deregulation and TP53 and RAS mutations are major events in poorly differentiated and undifferentiated thyroid carcinomas.

Background: Anaplastic thyroid carcinomas (ATCs) are among the most lethal malignancies, for which there is no effective treatment.

Objective: In the present study, we aimed to elucidate the molecular alterations contributing to ATC development and to identify novel therapeutic targets.

Design: We profiled the global gene expression of five ATCs and validated differentially expressed genes by quantitative RT-PCR in an independent set of tumors.