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 4 th 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.

Oral squamous cell carcinoma gene patterns connected with RNA methylation for prognostic prediction

“…PLK1 and AREG are highly expressed in HNSCC (Ling et al, 2021). Hagege et al reported that (Hagege et al, 2021) the expression of PLK1 was not determined by HPV status, which was consistent with our data. AREG , which is expressed when the DNA of stromal cells is damaged, induces programmed PD‐L1 expression in the receptor of carcinoma cells and produces immunologic suppression in the TME by activating the checkpoint to resist cytotoxic lymphocytes (Q. Xu, Long, et al, 2019).…”

Present and Future Perspective on PLK1 Inhibition in Cancer Treatment

“…PLK1 is reported to be overexpressed (at both mRNA and protein level) in many tumors compared to the normal tissue counterpart, and its overexpression has been associated with poor patient outcome ( 2 ). In addition, its overexpression has in some cases been associated with resistance to therapy and its inhibition to re-sensitization to chemo- and radio-therapy ( 3 – 5 ).…”

PLK1 and FoxM1 expressions positively correlate in papillary thyroid carcinoma and their combined inhibition results in synergistic anti‐tumor effects

“…PLK1 dysregulation has been reported in different tumor types and its overexpression has been associated poor patients' outcome, resistance to chemotherapy and radiotherapy [11,[36][37][38]. However, the role of PLK1 in PTC pathogenesis is unclear.…”