Pierre Roger

BRIEF OVERVIEW Pierre Roger pioneered the study of proliferation and differentiation of thyroid cells by defining model systems of primary cultures in chemically defined medium (without serum). Using these systems, he demonstrated and characterized the unique coexistence in these cells of two distinct proliferation modes, activated by TSH (only via cAMP elevation and PKA activation) or by several growth factors (via Ras, MAP kinase and PI3kinase cascades). The cAMP pathway simultaneously stimulates proliferation and differentiation expression in thyrocytes, and is involved in goitrigenesis and generation of hyperfunctional adenomas, whereas the growth factor pathways induce dedifferentiation and are involved in thyroid carcinomas. In thyroid primary cultures, the positive cell cycle regulation by cAMP is unique as it targets the assembly and then the activation of complexes formed by preexisting cyclin D3 and cyclin-dependent kinase (CDK) 4, without involving most intermediaries of classical mitogenic signaling cascades. ONGOING RESEARCH The present research interests of our group include the cellular and molecular features of cell cycle regulation in this model system and several others (investigation of cyclins, CDKs, their inhibitors, the interactions between these different proteins and their posttranslational modifications). Using two-dimensional electrophoresis to separate the phosphorylated forms of these proteins within their various complexes, we identified the activating phosphorylation of CDK4 as a direct crucial target for cell cycle regulation in various cell systems. Using various molecular, cellular, proteomic and bioinformatic approaches, we are currently (i) exploring the mechanisms of this critical CDK4 regulation that determines the inactivation of the central oncosuppressor protein pRb and the cell cycle decision in normal and cancerous cells; (ii) developing novel tools to predict whether cancer patients will benefit or not of treatments with the new CDK4 inhibitory drugs that are now approved for treatment of advanced ER+ breast cancers. CDK4 and CANCER As the master integrator of G1 phase cell cycle regulations, CDK4 is the first CDK to be activated in response to mitogenic stimuli and all their oncogenic perversions. Its main function is the inactivation of the pRb antioncogene (Rb1 gene). CDK4 activity requires its binding to a cyclin D (CCND1-3 genes) competed by INK4 CDK4 inhibitors such as p16 (CDKN2A-D). Genetic ablation of both CDK4 and CDK6 or of the three cyclins D permits normal cell cycles involved in development (due to cell cycle regulation plasticity and compensation by other CDKs (3)) but its deregulation causes addiction to CDK4 activity. Indeed, in different cancer models including breast cancers and NSC lung cancers, acute inhibition of CDK4/6 by the specific PD0332991 compound (Palbociclib) specifically induces either senescence or apoptotic cell death of tumoral cells. This and other CDK4/6 inhibitory drugs developed by Novartis (ribocliclib) or Eli Lilly (abemaciclib) are tested in a growing number of phase II/III clinical trials against various pRb-proficient chemotherapy-resistant cancers (90 studies with a total of 16000 patients are recorded in ClinicalTrials.gov). Despite mild dose-limiting side effects (cytopenia,..), palbociclib and ribociclib induce an ‘unprecedented improvement of progression-free survival’ of women with advanced ER-positive breast cancers, leading to the approval of palbociclib (FDA, Feb. 2015; EMA, Nov. 2016) and ribociclib (FDA, March 2017) as first-line treatments of advanced ER-positive breast cancer combined with endocrine therapy. Extension of CDK4/6 inhibitors to other cancers is limited by the lack of suitable biomarker of potential sensitivity.