Table 1.
Preclinical studies exploring the role of PI3K, AKT and/or mTOR inhibitors radiosensitising adenocarcinoma.
| Author | Year | Type of Cancer | Experimental Model | Drug (s) Tested | Drug Category | Radiotherapy Dose | Summary Outcome |
|---|---|---|---|---|---|---|---|
| Fatehi et al. [63] | 2018 | Breast | In vitro (cell line): MDA-MB231 | NVP-BEZ235 | PI3K and mTOR inhibitor | 2 Gy (Gamma radiation) | NVPBEZ235 related radiotherapy sensitivity significantly increased by IL-6 pre-treatment followed by exposure to sirtuin 1 inhibitor SRT1720 (p < 0.05) |
| Holler et al. [39] | 2016 | Breast | In vitro (cell line): MDA-MB-231 | Rapamycin | mTOR inhibitor | Variable range (0–5 Gy) | Rapamycin induced radioresistance in MDA-MB-231 breast cancer cells AKT knockdown by scramble sh-RNA or AKT1-shRNA leads to statistically significant Rrapamycin induced radiosensitisation |
| Kuger et al.(1) [64] | 2014 | Breast | In vitro (cell lines): MCF-7, MDA-MB-231 | NVP-BEZ235 | PI3K and mTOR inhibitor | Variable range (0–8 Gy) | Radiosensitisation observed independent of hypoxia Depleted levels of pAKT, inhibited HIF-1α expression, PI3K/mTOR signalling There was autophagy induction and delayed DNA repair |
| Miyasaka et al. [65] | 2015 | Endometrial | In vitro (cell lines): HEC-108, HEC-6, HEC-151, Ishikawa, HEC-59, HEC-50B,HEC-1B, HEC-116 | NVP-BEZ235 | PI3K and mTOR inhibitor | Variable range (2–6 Gy) | Suppression of the HIF1-α/VEGF pathway Targeting the PI3K/mTOR or HIF-1α pathways could improve radiosensitivity |
| Chen et al. (2) [48] | 2019 | CRC | In vitro (cell lines): HCT 116, HT 29, SW480 In vivo (xenograft): HCT-116 + mice |
NVP-BEZ235 (maintenance therapy) | PI3K and mTOR inhibitor | Variable range (1–5 Gy) | Enhanced apoptosis Prolonged inhibition of cellular viability Disruption of DSB repair pathways |
| Djuzenova et al. [49] | 2016 | CRC | In vitro (cell lines): SW480, SW48 | PI-103 (+ NVP-AUY922) |
PI3K, mTOR, DNA-PK inhibitor HSP-90 inhibitor |
Variable range (0–8 Gy) | Enhanced radiosensitising effect following treatment when treatment started 3 h before radiotherapy and continued for 24 h after radiotherapy |
| Chen et al. (1) [18] | 2015 | CRC | In vitro (cell lines): HCT 116, SW 620 (KRAS mutant), HT 29 (KRAS wild type) In vivo (xenograft): HCT-116 + mice |
NVP-BEZ235 | PI3K and mTOR inhibitor | Variable range (0–6 Gy) |
Dose dependent increase in radiotherapy sensitivity and increased apoptosis after treatment with drug and radiotherapy Loss of expression of proteins responsible for DNA damage repair, cell growth and proliferation Significant reduction in xenograft tumour size |
| Prevo et al. [23] | 2008 | CRC | In vitro (cell lines): HCT116, DLD-1 | PI-103 | PI3K, mTOR and DNA-PK inhibitor | Variable range (0–6 Gy) |
Reduced AKT phosphorylation Radiosensitisation independent of PI3K overexpression, EGFR and RAS mutation status |
| Manegold et al. [50] | 2008 | CRC and Pancreatic Cancer |
In vitro (cell line): CT-26 (murine CRC) L3.6pl (human pancreatic) In vivo (xenograft): CT-26/L3.6pl + mice |
Everolimus | mTOR inhibitor | 10 Gy or 20 Gy | Radiosensitising effects observed. Significant reduction in tumour size of pancreatic and CRC cell xenografted mice treated with drug and radiotherapy compared to control (p < 0.05) |
| Park et al. [66] | 2017 | Pancreatic Cancer | In vitro (cell lines): Miapaca-2, PANC-1 In vivo (xenograft): Miapaca-2 + mice |
HS-173 | PI3K inhibitor | Variable range (0–10Gy) |
G2/M cell cycle arrestM Inhibited Ataxia-Telangiectasia Mutated (ATM) protein and DNA-PKcs Improved radiotherapy response by inhibiting the DNA damage-repair pathways |
| Dumont et al. [60] | 2019 | Prostate Cancer | In vivo (xenograft): PC-3 + mice | Rapamycin | mTOR inhibitor | Radioisotope treatment (Lu-labeled GRPr antagonist) Dose—37 MBq (for 72 h) | Rapamycin alone had no effect. With rapamycin and GRPr antagonist, more effective radiosensitisation observed in xenografts |
| Chang et al. [56] | 2014 | Prostate Cancer | In vitro (cell line): CAP-RR | BKM120 Rapamycin NVP-BEZ235 PI-103 | PI3K Inhibitor mTOR inhibitorPI3K and mTOR inhibitor PI3K, mTOR and DNA-PK inhibitor |
6 Gy | Dual inhibitors superior at radiosensitising – increased apoptosis and autophagy Dual inhibition led to G2/M arrest and suppressed DSB repair mechanisms |
| Potiron et al. [57] | 2013 | Prostate Cancer | In vitro (cell lines): PC-3, DU 145 | NVP-BEZ235 | PI3K and mTOR inhibitor | Variable range (0–12.5 Gy) | Radiosensitised both cell lines independent of oxygen concentration or PTEN mutation status G2/M arrest |
| Zhu et al. [58] | 2013 | Prostate Cancer | In vitro (cell line): PC-3 | NVP-BEZ235 | PI3K and mTOR inhibitor | Variable range (0–10 Gy) | Radiosensitising effects on PC3 cell line after treatment G2/M arrest |
| Diaz et al. [59] | 2009 | Prostate Cancer | In vitro (cell lines): NCI-60 prostate cancer cell line panel In vivo (xenograft): PC-3 + mice |
Palomid 529 | AKT inhibitor | Variable range (2–8 Gy) | Decreased expression of proteins involved in cell survival and proliferation Xenografts demonstrated greater tumour shrinkage (77.4%) after treatment |