ATM, ATR and DNA-PKcs expressions correlate to adverse clinical outcomes in epithelial ovarian cancers

Abstract

BackgroundAtaxia-telangiectasia mutated (ATM), ataxia-telangiectasia mutated and rad3 related (ATR) and DNA-dependent protein kinase catalytic sub-unit (DNA-PKcs) play critical roles in DNA damage response (DDR) by linking DNA damage sensing to DDR effectors that regulate cell cycle progression and DNA repair. Our objective was to evaluate if ATM, ATR and DNA-PKcs expressions could predict response to therapy and clinical outcome in epithelial ovarian cancers.MethodsWe investigated ATM, ATR, and DNA-PKcs expressions in ovarian epithelial cancers [protein expression (n = 194 patients), mRNA expression (n = 156 patients)] and correlated to clinicopathological outcomes as well as expression of X-ray repair cross-complementing protein 1 (XRCC1), cell division cycle-45 (CDC45), cyclin-dependent kinase 1(CDK1) and Ki-67 in tumours.ResultsHigh ATM protein expression was associated with serous cystadenocarcinomas (p = 0.021) and platinum resistance (p = 0.017). High DNA-PKcs protein expression was associated with serous cystadenocarcinomas (p = 0.006) and advanced stage tumours (p = 0.018). High ATM protein (p = 0.001), high ATM mRNA (p = 0.018), high DNA-PKcs protein (p = 0.002), high DNA-PKcs mRNA (p = 0.044) and high ATR protein (p = 0.001) expressions are correlated with poor ovarian cancer specific survival (OCSS). In multivariate Cox model, high DNA-PKcs (p = 0.006) and high ATR (p = 0.043) protein expressions remain independently associated with poor OCSS.ConclusionsATM, ATR and DNA-PKcs expressions may have prognostic and predictive significances in epithelial ovarian cancer.General significanceThe data presented here provides evidence that ATM, ATR and DNA-PKcs involved in DDR are not only promising biomarkers but are also rational targets for personalized therapy in ovarian cancer.

Signal Transduction Pathways in Breast Cancer: The Important Role of PI3K/Akt/mTOR

“…Here, it is important to discuss the role of mTOR inhibitors and their relationship with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), another key component of the DDR system. Low levels of DNA-PKcs protein expression were related to higher tumour grade, dedifferentiation and mitotic index, and poor survival [73,109]. CC-115, a dual inhibitor of mTOR and DNA-PKcs, has been shown to inhibit cell growth in vitro by blocking DDR pathways, thus inducing apoptosis in many cancer lines, including breast cancer cells [110].…”

The Role of the Core Non-Homologous End Joining Factors in Carcinogenesis and Cancer

“…DNA-PKcs has also been classified as a candidate driver in hepatocarcinogensis, with amplification of the PRKDC locus, increased mRNA expression, and increased autophosphorylation at serine 2056 correlating with poor survival [ 100 ]. In the case of serous cystadenocarcinomas and ovarian cancer, high DNA-PKcs mRNA and protein levels correlated with poor survival [ 176 ]. Preclinical findings have also identified DNA-PKcs as a potential driver of pro-metastatic signaling via transcriptional regulation in castration-resistant prostate cancer [ 177 ].…”

Inhibition of the DNA-Dependent Protein Kinase for Cancer Therapy

“…Studies in chronic lymphocytic leukaemia (CLL) have demonstrated that increased DNA-PKcs activity correlated with resistance to DNA damage inducing chemotherapeutics and reduced treatment free interval [9,10]. Elevated DNA-PKcs expression has also been reported in gastric cancer [11] and found to correlate with poor patient prognosis in ovarian cancer [12] and hepatocellular carcinoma (HCC) [13]. The evidence identifying DNA-PK as a key marker for treatment resistant tumours has driven many attempts to find suitable inhibitors of DNA-PKcs kinase activity.…”