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

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.

KRAS as a Key Oncogene in the Clinical Precision Diagnosis and Treatment of Pancreatic Cancer

“…Studies have also shown that targeted inhibition of the PI3K-AKT-mTOR pathway can prevent cell repair of DNA damage, thereby making patients more sensitive to radiotherapy and chemotherapy [134]. This finding has been used to treat head and neck malignancies [135,136]. Besides, inhibition of PI3K-AKT-mTOR pathway in pancreatic cancer cells can inhibit cancer-associated fibroblasts (CAF), reduce interstitial fibrosis, and alter pancreatic cancer tumor microenvironment (TME), which will thereby increase the lethality of chemotherapy drugs [137].…”

Recommendations for the use of biomarkers for head and neck cancer, including salivary gland tumours: a consensus of the Spanish Society of Medical Oncology and the Spanish Society of Pathology

“…The presence of alterations in this pathway is related to a poor prognosis and resistance to radiotherapy and cytostatic drugs. Preclinical and phase II trials of PI3K/AKT/mTOR inhibitors (buparlisib and alpelisib) have demonstrated efficacy in monotherapy and in combination with chemotherapy [71,72] and radiotherapy [73][74][75]. In general, ongoing clinical trials are trying to elucidate the role of AKT and mTOR inhibitors in combination with chemotherapy and radiotherapy and in patients with resistance to them.…”

PIK3CAMutations Drive Therapeutic Resistance in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

“…Additionally, SGI-1776 and AZD-1208 (PIM kinase inhibitors) may overcome/delay resistance to alpelisib and produce additive/synergistic effects in tumor inhibition. [104][105][106][107][108][109][110][111][112][113] As it is pertinent to breast cancer, alpelisib was synergistic with the CKD4/6 inhibitor ribociclib in triple-negative cell lines and PDX models, 108 and showed synergy with the pan-HER TKI neratinib in inhibiting growth of HER2+ cell lines. 113 In summary, development of a biomarker for PI3Ki is an evolving field.…”