The Polo-like kinase 1 inhibitor onvansertib represents a relevant treatment for head and neck squamous cell carcinoma resistant to cisplatin and radiotherapy.

Abstract

Rationale: Head and neck squamous cell carcinoma (HNSCC) represent the 4th most aggressive cancer. 50% of patients relapse to the current treatments combining surgery, radiotherapy and cisplatin and die two years after the diagnosis. Elevated expression of the polo-like kinase 1 (Plk1) correlated to a poor prognosis in epidermoid carcinomas. Methods: The molecular links between Plk1 and resistance to cisplatin/radiotherapy were investigated in patients and cell lines resistant to cisplatin and/or to radiotherapy. The therapeutic relevance of the Plk1 inhibitor onvansertib, alone or combined with cisplatin/radiotherapy, was evaluated on the proliferation/migration on HNSCC cell lines, in experimental HNSCC in mice, in a zebrafish metastasis model and on patient-derived 3D tumor sections. Results: Plk1 expression correlated to a bad prognosis in HNSCC and increased after relapse on cisplatin/radiotherapy. Onvansertib induced mitotic arrest, chromosomic abnormalities and polyploidy leading to apoptosis of sensitive and resistant HNSCC cells at nanomolar concentrations without any effects on normal cells. Onvansertib inhibited the growth of experimental HNSCC in mice and metastatic dissemination in zebrafishes. Moreover, onvansertib combined to cisplatin and/or radiotherapy resulted in a synergic induction of tumor cell death. The efficacy of onvansertib alone and in combination with reference treatments was confirmed on 3D viable sections of HNSCC surgical specimens. Conclusions: Targeting Plk1 by onvansertib represents a new strategy for HNSCC patients at the diagnosis in combination with reference treatments, or alone as a second line treatment for HNCSCC patients experiencing relapses.

• Authors: Anais Hagege, Damien Ambrosetti, Julien Boyer, Alexandre Bozec, Jérôme Doyen, Emmanuel Chamorey, Xingkang He, Isabelle Bourget, Julie Rousset, Esma Saada, Olivia Rastoin, Julien Parola, Frederic Luciano, Yihai Cao, Gilles Pagès, Maeva Dufies
• Journal: Theranostics (Theranostics) Vol. 11 Issue 19 Pg. 9571-9586 ( 2021) ISSN: 1838-7640 [Electronic] Australia
• PMID: 34646387 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Cell Cycle Proteins
• Piperazines
• Proto-Oncogene Proteins
• Pyrazoles
• Quinazolines
• onvansertib
• Protein Serine-Threonine Kinases
• Cisplatin

Topics

• Animals
• Apoptosis (drug effects)
• Carcinoma, Squamous Cell (pathology)
• Cell Cycle Proteins (antagonists & inhibitors, metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cisplatin (therapeutic use)
• Disease Models, Animal
• Drug Resistance, Neoplasm (drug effects)
• Female
• Gene Expression (genetics)
• Gene Expression Regulation, Neoplastic (genetics)
• Head and Neck Neoplasms (drug therapy)
• Humans
• Mice
• Mice, Nude
• Neoplasm Recurrence, Local (drug therapy)
• Piperazines (metabolism, therapeutic use)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins (antagonists & inhibitors, metabolism)
• Pyrazoles (metabolism, therapeutic use)
• Quinazolines (metabolism, therapeutic use)
• Radiotherapy (methods)
• Squamous Cell Carcinoma of Head and Neck (drug therapy, metabolism)
• Zebrafish
• Polo-Like Kinase 1