The impact of DNA damage repair inhibitors on the therapeutic window of thoracic radiation

Background: Lung cancer is the leading cause of cancer death worldwide. A mainstay of treatment is radiotherapy, although its efficacy is limited by toxicity to surrounding normal tissue. New combination treatments are being proposed to increase the radiotherapy anti-tumour effect, but there has been a lack of preclinical studies looking at normal tissue effects simultaneously. Aim: To address the need for a mouse model of anti-tumour and normal tissue responses concurrently over an appropriate time-course for early and late tissue effects, we evaluated the A/J model of chemically-induced lung carcinoma. Methods: Autochthonous lung tumours were induced by urethane treatment of A/J mice. Tumour bearing animals were treated with whole thorax, hemithorax, or CT- guided left lung ionising radiation (IR, 10 Gy, 13 Gy, or 15 Gy single dose or 5 x 5 Gy fractionated dose) alone or in combination with DNA damage response (DDR) inhibitors (AZD6738, AZD7648, AZD1390) at different time points during tumour development. Tumour and normal tissue responses were followed for up to 26 weeks. Lungs were collected and processed for histology, and Masson’s trichrome staining was performed to evaluate collagen deposition in irradiated lungs. Magnetic resonance images of lung and tumours were obtained during the course of the experiments. Results: Whole thorax IR combined with DDR inhibitors resulted in oesophageal inflammation and immune cell infiltration, so hemithorax fractionated and single dose IR protocols were developed. Hemithorax IR combined with an ATR inhibitor (AZD6738) had limited anti-tumour effects but also few normal tissue responses. In contrast, hemithorax IR combined with a DNA-PK inhibitor (AZD7648) led to significant anti-tumour effects but also was associated with increased skin and lung normal tissue damage. Furthermore, hemithorax IR combined with an ATM inhibitor (AZD1390) resulted in limited anti-tumour effects and also skin and lung normal tissue damage. Early oesophageal modelling of fractionated whole ...