ATM Kinase Inhibition Preferentially Sensitises PTEN-Deficient Prostate Tumour Cells to Ionising Radiation

Simple Summary: Prostate cancer is the most frequently diagnosed cancer in men. Despite the importance of radical radiotherapy for the management of this disease, recurrence remains a challenge. PTEN is a tumour suppressor that is frequently inactivated in advanced prostate cancer and has been associated with relapse following radiotherapy. The present study shows that the role of PTEN in response to ionizing radiation is complex. Furthermore, it demonstrates that in the absence of PTEN, an increased response to combined treatment using radiotherapy and the ATM inhibitor KU-60019 can be observed. Our findings provide a strong rationale for evaluating loss of PTEN in prostate cancer as a therapeutic target for ATM inhibitor in combination with radiotherapy in the clinical setting. Radical radiotherapy, often in combination with hormone ablation, is a safe and effective treatment option for localised or locally-advanced prostate cancer. However, up to 30% of patients with locally advanced PCa will go on to develop biochemical failure, within 5 years, following initial radiotherapy. Improving radiotherapy response is clinically important since patients exhibiting biochemical failure develop castrate-resistant metastatic disease for which there is no curative therapy and median survival is 8-18 months. The aim of this research was to determine if loss of PTEN (highly prevalent in advanced prostate cancer) is a novel therapeutic target in the treatment of advanced prostate cancer. Previous work has demonstrated PTEN-deficient cells are sensitised to inhibitors of ATM, a key regulator in the response to DSBs. Here, we have shown the role of PTEN in cellular response to IR was both complex and context-dependent. Secondly, we have confirmed ATM inhibition in PTEN-depleted cell models, enhances ionising radiation-induced cell killing with minimal toxicity to normal prostate RWPE-1 cells. Furthermore, combined treatment significantly inhibited PTEN-deficient tumour growth compared to PTEN-expressing counterparts, with minimal toxicity observed. We have further shown PTEN loss is accompanied by increased endogenous levels of ROS and DNA damage. Taken together, these findings provide pre-clinical data for future clinical evaluation of ATM inhibitors as a neoadjuvant/adjuvant in combination with radiation therapy in prostate cancer patients harbouring PTEN mutations.

Automated summary

Prostate cancer is the most frequently diagnosed cancer in men, with the role of the PTEN gene being complex but important in its treatment. Studies suggest that in the absence of PTEN, combined treatment using radiotherapy and the ATM inhibitor KU-60019 has a greater therapeutic effect.