1. PTEN Depletion Increases Radiosensitivity in Response to Ataxia Telangiectasia-Related-3 (ATR) Inhibition in Non-Small Cell Lung Cancer (NSCLC).
- Author
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Dunne VL, Ghita-Pettigrew M, Redmond KM, Small DM, Weldon S, Taggart CC, Prise KM, Hanna GG, and Butterworth KT
- Subjects
- Animals, Humans, Mice, Cell Line, Tumor, Pyrazines pharmacology, Pyrazines therapeutic use, Xenograft Model Antitumor Assays, DNA Repair drug effects, Indoles, Morpholines, Sulfonamides, PTEN Phosphohydrolase metabolism, PTEN Phosphohydrolase genetics, Carcinoma, Non-Small-Cell Lung radiotherapy, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms metabolism, Lung Neoplasms pathology, Lung Neoplasms radiotherapy, Lung Neoplasms genetics, Lung Neoplasms drug therapy, Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors, Ataxia Telangiectasia Mutated Proteins metabolism, Ataxia Telangiectasia Mutated Proteins genetics, Radiation Tolerance drug effects, Pyrimidines pharmacology, Pyrimidines therapeutic use
- Abstract
Radiotherapy (RT) treatment is an important strategy for the management of non-small cell lung cancer (NSCLC). Local recurrence amongst patients with late-stage NSCLC remains a challenge. The loss of PTEN has been associated with radio-resistance. This study aimed to examine the efficacy of RT combined with ataxia telangiectasia-mutated Rad3-related (ATR) inhibition using Ceralasertib in phosphatase and tensin homolog (PTEN)-depleted NSCLC cells and to assess early inflammatory responses indicative of radiation pneumonitis (RP) after combined-modality treatment. Small hairpin RNA (shRNA) transfections were used to generate H460 and A549 PTEN-depleted models. Ceralasertib was evaluated as a single agent and in combination with RT in vitro and in vivo. Histological staining was used to assess immune cell infiltration in pneumonitis-prone C3H/NeJ mice. Here, we report that the inhibition of ATR in combination with RT caused a significant reduction in PTEN-depleted NSCLC cells, with delayed DNA repair and reduced cell viability, as shown by an increase in cells in Sub G1. Combination treatment in vivo significantly inhibited H460 PTEN-depleted tumour growth in comparison to H460 non-targeting PTEN-expressing (NT) cell-line-derived xenografts (CDXs). Additionally, there was no significant increase in infiltrating macrophages or neutrophils except at 4 weeks, whereby combination treatment significantly increased macrophage levels relative to RT alone. Overall, our study demonstrates that ceralasertib and RT combined preferentially sensitises PTEN-depleted NSCLC models in vitro and in vivo, with no impact on early inflammatory response indicative of RP. These findings provide a rationale for evaluating ATR inhibition in combination with RT in NSCLC patients with PTEN mutations.
- Published
- 2024
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