PI3k inhibitors (BKM120 and BYL719) as radiosensitizers for head and neck squamous cell carcinoma during radiotherapy.

Fu-Cheng Chuang,Yu-Chieh Su,Chih-Chun Wang,Shyh-An Yeh,Tzer-Zen Hwang,Jian-Han Chen,Salvatore V Pizzo

doi:10.1371/journal.pone.0245715

Fu-Cheng Chuang, Yu-Chieh Su + Show 5 more

Open Access

https://doi.org/10.1371/journal.pone.0245715

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Journal: PloS one	Publication Date: Jan 20, 2021
Citations: 13	License type: CC BY 4.0

Affiliation: I-Shou University, E-Da Hospital

Abstract

Approximately 500,000 new cases of head and neck squamous cell carcinoma (HNSCC) are reported annually. Radiation therapy is an important treatment for oral squamous cell carcinoma (OSCC). The survival rate of patients with HNSCC remained low (50%) in decades because of radiation therapy failure caused by the radioresistance of HNSCC cells. This study aimed to identify PI3K inhibitors that can enhance radiosensitivity. Results showed that pan-Phosphoinositide 3-kinases (PI3K) inhibitor BKM120 and class I α-specific PI3K inhibitor BYL719 dose-dependently reduced the growth of OSCC cells but not that of radioresistant OML1-R cells. The combination treatment of BKM120 or BYL719 with radiation showed an enhanced inhibitory effect on OSCC cells and radioresistant OML1-R cells. Furthermore, the enhanced inhibitory effect of the combination treatment was confirmed in patient-derived OSCC cells. The triple combination treatment of mTOR inhibitor AZD2014 and BKM120 or AZD2014 and BYL719 with radiation showed a significantly enhanced inhibitory effect on radioresistant OML1-R cells. These results suggest that the PI3K inhibitors are potential therapeutic agents with radiosensitivity for patients with OSCC.

Highlights

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer worldwide, remaining a public health concern with an estimated annual incidence of 500,000 new cases [1]
The results indicated that pan-Phosphoinositide 3-kinases (PI3K) inhibitor BKM120 may be a better inhibitor against oral squamous cell carcinoma (OSCC) cell growth than BYL719
OSCC (SCC4 and SCC25), OML1, and OML-R were pretreated with the inhibitors and irradiated at 0 and 4 Gy to investigate whether BYL719 and BKM120 can sensitize OSCC cells to ionizing radiation (IR) and reduce IR-induced radioresistance

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer worldwide, remaining a public health concern with an estimated annual incidence of 500,000 new cases [1]. 90% head and neck cancer are squamous cell carcinoma and appear in upper aerodigestive tract organs, such as oral cavity, larynx, and pharynx [2]. Despite the improvement in HNSCC diagnosis and treatment through radiation, surgery, chemotherapy, concurrent chemoradiation, and monoclonal antibodies, the 5-year survival of patients with HNSS remains low at 40% [3]. Locoregional, distant relapse, and regional recurrences resistant to tumor therapies are the main reason of death in patients with HNSCC [4]. Recurrent tumors arise from radiation-resistant carcinoma cells, leading to re-irradiation treatment failure [5].

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