Abstract
Simple SummaryProstate 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.
Highlights
External beam radiotherapy is a well-established treatment option for locally advanced prostate cancer (PCa)
The α and β radiobiological parameters for each of the curves in Figure 1, in addition to the surviving fraction at 2 Gy (SF2) and 4 Gy (SF4) values are summarised in Supplementary Table S1
sensitisation enhancement ratio (SER) was 0.68, indicating loss of phosphatase and tensin homolog (PTEN) significantly sensitised these cells to ionising radiation (IR)
Summary
External beam radiotherapy is a well-established treatment option for locally advanced prostate cancer (PCa). Despite the high rates of local tumour control, radioresistance is observed in approximately 20–30% of localised PCa patients following initial radiotherapy, leading to cancer-related mortality in up to 27% of patients within 5 years [1]. There is a significant clinical need to identify robust tissue biomarkers that will help predict a patient’s outcome following radiotherapy. Such biomarkers may help achieve better tumour response in high-risk patients by selecting patients for more effective personalised treatment plans combining molecularly targeted drugs. PTEN loss has further been shown to be a prognostic factor for relapse following radiotherapy in locally advanced PCa [3]. AKT hyperactivation, a result of PTEN loss and deregulation of the PI3K/AKT pathway, correlates with
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