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

Abstract

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 (n ¼ 8) and patient-derived tumor xenograft (PDTX) models (n ¼ 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 0 -G 1 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.

Combination of miR‑143 and miR‑506 reduces lung and pancreatic cancer cell growth through the downregulation of cyclin‑dependent kinases

“…We transfected the cells, as described above, and performed the PI staining method to analyze the cell cycle phase of the cells. For comparison, we utilized two cell cycle inhibitors, ribociclib at 3 µM (42,43) and flavopiridol at 100 nM (44,45). Ribociclib is an FDA-approved, clinically used CDK4/6 inhibitor, and flavopiridol is a clinically tested CDK1, CDK2, CDK4, and CDK7 inhibitor (43,44,46).…”

Protein O‐GlcNAcylation levels are regulated independently of dietary intake in a tissue and time‐specific manner during rat postnatal development

“…We show that O ‐GlcNAc levels decrease at birth, which is the first metabolic transition. Other physiological changes at birth, such as going from a low oxygen environment in utero to higher arterial oxygen content, could potentially cause this variation 21 . A second metabolic transition occurs at weaning.…”

The Renaissance of Cyclin Dependent Kinase Inhibitors

“…The mode of action of ribociclib, also known as LEE011, has been investigated in numerous in vitro studies, particularly in cancers such as leukemia [ 148 ], neuroblastoma [ 149 ], neuroendocrine tumors [ 150 ], liposarcomas [ 151 ], breast cancer [ 152 ] and HNSCC [ 153 ].…”