Preclinical Activity of Ribociclib in Squamous Cell Carcinoma of the Head and Neck

• Published in: Molecular cancer therapeutics Vol. 19; no. 3; pp. 777 - 789
• Main Authors: van Caloen, Gabrielle, Schmitz, Sandra, El Baroudi, Mariama, Caignet, Xavier, Pyr dit Ruys, Sébastien, Roger, Pierre P., Vertommen, Didier, Machiels, Jean-Pascal
• Format: Journal Article
• Language: English
• Published: United States 01.03.2020
• Subjects: Aminopyridines - pharmacology; Animals; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cell Cycle; Cell Movement; Cell Proliferation; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Epithelial-Mesenchymal Transition; Female; Forkhead Box Protein M1 - genetics; Forkhead Box Protein M1 - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Humans; Mice; Mice, Nude; Purines - pharmacology; Retinoblastoma Protein - genetics; Retinoblastoma Protein - metabolism; Squamous Cell Carcinoma of Head and Neck - drug therapy; Squamous Cell Carcinoma of Head and Neck - metabolism; Squamous Cell Carcinoma of Head and Neck - pathology; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514; 1538-8514
• DOI: 10.1158/1535-7163.MCT-19-0695

Cell-cycle pathway impairments resulting in CDK4 and 6 activation are frequently observed in human papillomavirus (HPV)-negative squamous cell carcinoma of the head and neck (SCCHN). We investigated the activity of ribociclib, a CDK4/6 inhibitor, in SCCHN models with the aim of identifying predictive biomarkers of response. HPV-negative or HPV-positive SCCHN cell lines ( = 8) and patient-derived tumor xenograft (PDTX) models ( = 6) were used. The models were classified according to their sensitivity to ribociclib to investigate potential predictive biomarkers. Ribociclib had a cytostatic effect in some HPV-negative SCCHN models but had no effect in HPV-positive models. In SCCHN cell lines and PDTXs, the retinoblastoma (Rb) protein expression level correlated with ribociclib activity. Rb knockdown was, however, not sufficient to block G -G arrest induced by ribociclib in Detroit-562 where p107, p130, and Forkhead BOX M1 (FOXM1) were also implicated in ribociclib activity. Cell lines harboring epithelial-to-mesenchymal transition (EMT) features were less sensitive to ribociclib than those with an epithelial phenotype. Rb downregulation induced EMT in our Rb-expressing SCCHN cell lines. However, ribociclib still had significant activity in one PDTX model with high Rb and vimentin expression, suggesting that the presence of vimentin alone is not enough to induce ribociclib resistance. These findings suggest that CDK4/6 inhibitors should be investigated in patients with HPV-negative SCCHN with high Rb expression and an epithelial phenotype. Although these biomarkers are not predictive in all cases, they may enrich the population that could benefit from CDK4/6 inhibitors.