Effect of sorafenib on cisplatin-based chemoradiation in head and neck cancer cells

Abstract

Despite aggressive chemoradiation (CRT) protocols in the treatment of patients with head and neck squamous cell carcinomas (HNSCC), the outcome is still unfavorable. To improve therapy efficacy we had already successfully tested the multikinase inhibitor sorafenib in combination with irradiation (IR) in previous studies on HNSCC cell lines. In this study we investigated its effect on combined CRT treatment using cisplatin.Radio- and chemosensitivity with and without sorafenib was measured in four HNSCC cell lines and normal fibroblasts (NF) by colony formation assay. Apoptosis and cell cycle analysis were performed by flow cytometry.In HNSCC cells, sorafenib enhanced the antiproliferative effect of cisplatin without affecting apoptosis induction and with only minor effects on cell inactivation. Sorafenib added prior to irradiation enhanced cellular radiosensitivity in three of the tested HNSCC cell lines and caused massive overall cell inactivation when combined with CRT. In contrast, sorafenib did not radiosensitize NF and reduced cisplatin-induced cell inactivation. Cell inactivation by IR and cisplatin is further increased by the addition of sorafenib in HNSCC, but not in NF cells. Therefore, sorafenib is a promising candidate to improve therapy efficacy for HNSCC.

Receptor tyrosine kinase MET as potential target of multi‐kinase inhibitor and radiosensitizer sorafenib in HNSCC

“…As reported previously, sorafenib inhibits cell proliferation (Figure A), induces significant cell inactivation (Figure B) and radiosensitizes HNSCC responder cells such as UT‐SCC 42B (Figure C) causing a massive overall cell inactivation (Supporting Information Figure S1A). To identify the kinase(s), whose inhibition might be responsible for this radiosensitization, we first analyzed the effect of sorafenib on well‐described targets such as Raf or PDGF receptor .…”

“…In this context, we have demonstrated that the small molecule inhibitor sorafenib causes significant cell inactivation and growth retardation in HNSCC cells . Although not interacting with cisplatin‐mediated cell inactivation, sorafenib enhances the efficacy of X‐irradiation, leading to radiosensitization and a striking overall cell kill . Sorafenib‐mediated radiosensitization of cancer cells is probably caused by compromised DNA repair and can be observed in various other entities such as colorectal, liver, or breast cancer .…”

“…In this context, we have demonstrated that the small molecule inhibitor sorafenib causes significant cell inactivation and growth retardation in HNSCC cells . Although not interacting with cisplatin‐mediated cell inactivation, sorafenib enhances the efficacy of X‐irradiation, leading to radiosensitization and a striking overall cell kill .…”

“…It is not, however, a general phenomenon because glioblastoma cells were not sensitized . Additionally, although its effects on proliferation and cell inactivation without irradiation can be observed in every tested HNSCC cell line, radiosensitization can only be observed in selected cell lines, arguing for 2 groups of HNSCC, responding and nonresponding cell lines in terms of sorafenib‐mediated radiosensitization . Because the use of sorafenib as a monotherapy did not achieve a convincing therapeutic effect in HNSCC, sorafenib may only be clinically useful as a radiosensitizer for responsive tumors.…”

DNA Repair

“…Other cell signalling factors that could be promising targets for DSB repair modulation include MAPK and AKT signalling (Kriegs et al 2010;Toulany et al 2006). Furthermore, EGFR-independent targets are being investigated, such as the proto-oncogenes Myc and Ras, and the therapeutic potential of multi-kinase inhibitors such as imatinib, dasatinib or sorafenib is being explored, with promising early results Möckelmann et al 2016). However, it is not at all clear at this stage whether DNA repair plays a significant role in these treatment strategies.…”