Radiosensitising Cancer Using Phosphatidylinositol-3-Kinase (PI3K), Protein Kinase B (AKT) or Mammalian Target of Rapamycin (mTOR) Inhibitors

Abstract

Radiotherapy is routinely used as a neoadjuvant, adjuvant or palliative treatment in various cancers. There is significant variation in clinical response to radiotherapy with or without traditional chemotherapy. Patients with a good response to radiotherapy demonstrate better clinical outcomes universally across different cancers. The PI3K/AKT/mTOR pathway upregulation has been linked to radiotherapy resistance. We reviewed the current literature exploring the role of inhibiting targets along this pathway, in enhancing radiotherapy response. We identified several studies using in vitro cancer cell lines, in vivo tumour xenografts and a few Phase I/II clinical trials. Most of the current evidence in this area comes from glioblastoma multiforme, non-small cell lung cancer, head and neck cancer, colorectal cancer, and prostate cancer. The biological basis for radiosensitivity following pathway inhibition was through inhibited DNA double strand break repair, inhibited cell proliferation, enhanced apoptosis and autophagy as well as tumour microenvironment changes. Dual PI3K/mTOR inhibition consistently demonstrated radiosensitisation of all types of cancer cells. Single pathway component inhibitors and other inhibitor combinations yielded variable outcomes especially within early clinical trials. There is ample evidence from preclinical studies to suggest that direct pharmacological inhibition of the PI3K/AKT/mTOR pathway components can radiosensitise different types of cancer cells. We recommend that future in vitro and in vivo research in this field should focus on dual PI3K/mTOR inhibitors. Early clinical trials are needed to assess the feasibility and efficacy of these dual inhibitors in combination with radiotherapy in brain, lung, head and neck, breast, prostate and rectal cancer patients.

Transcriptomic analysis of breast cancer patients sensitive and resistant to chemotherapy: Looking for overall survival and drug resistance biomarkers

“…Activation of PI3K/AKT has been related to breast cancer and currently, there is a lot of interest in the development of inhibitors of this pathway to target breast cancer 14 . Besides, PI3K/AKT/mTOR pathway upregulation has been linked to chemotherapy and radiotherapy resistance 15 and its inhibition overcome drug resistance in breast cancer cells 16,17 . Another pathway suggested by our analysis was the MAPK pathway.…”

MicroRNA Profiling in Oesophageal Adenocarcinoma Cell Lines and Patient Serum Samples Reveals a Role for miR-451a in Radiation Resistance

“…miR-451a is a known and established regulator of the PI3K/AKT pathway via downstream targets like AMPK [ 87 , 88 ]. In this context, the PI pathway has been linked to resistance to radiation, and inhibitors of this pathway are currently being trialled in an attempt to restore radiation sensitivity in different cancer types [ 89 ]. An involvement of miR-451a activated PI3K/AKT pathway in the resistance to radiation therefore seems likely in OAC.…”

Activation of PI3K/AKT/mTOR Pathway Causes Drug Resistance in Breast Cancer

“…Aberrant upregulation and activation of PI3K/AKT/mTOR pathway is also correlated with resistance radiotherapy. A number of preclinical studies indicated that inhibition of PI3K/AKT/mTOR pathway can sensitize different types of cancer cells, including non-small cell lung cancer, breast cancer, nasopharyngeal carcinoma, oral squamous, and head and neck cancer, to radiotherapy ( Yu et al, 2017 ; Chen et al, 2020b ; Chen et al, 2020c ; Glorieux et al, 2020 ; Schötz et al, 2020 ; Wanigasooriya et al, 2020 ). In breast cancer, IL-6 pre-treatment followed by SIRT1 activation by SRT1720 combined with dual PI3K/mTOR inhibitor NVP-BEZ235 obviously increased sensitivity of the cancer stem cells to radiation, so that late stage breast cancer cells therapeutic effect was effectively improved ( Fatehi et al, 2018 ; Masoumi et al, 2020 ).…”