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    • br Funding This study was supported

    2022-11-18


    Funding This study was supported by Grant UM1-CA186690 (NCI-CTEP) and R01CA204173 (CJB). This project used the UPCI Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF) and was supported in part by award P30-CA47904 and R50CA211241.
    Introduction Despite the efficacy of platinum based chemotherapy, the overall prognosis for patients with advanced ovarian cancer remains poor [1], [2], [3]. Resistance to platinating agents (carboplatin, cisplatin) is a formidable clinical problem and may be directly related to proficient DNA damage signalling and DNA repair in cancer cells [4], [5]. ATM (ataxia-telangiectasia mutated), ATR (ataxia-telangiectasia mutated and Rad3 related) kinases and DNA-PKcs (DNA-dependent protein kinase catalytic sub-unit) play critical roles in the DNA damage response (DDR) and link DNA damage sensing to DDR effectors that regulate fgfr1 progression and DNA repair [6], [7], [8], [9], [10], [11], [12], [13], [14]. Whereas ATM and DNA-PK are predominantly activated by DNA double strand breaks (DSBs) [6], [7], [8], [9], [12], ATR is activated in response to a number of DNA damaging lesions that involve single-stranded (SS)–double-stranded (DS) junctions such as those generated when replication fork encounters a DNA lesion or during nucleotide excision repair or during resection of a DSB [10], [11], [13], [14]. Activated ATR and ATM phosphorylate Chk1 or Chk2 respectively. This in turn modulates a number of other proteins involved in DNA repair, cell cycle control and apoptosis [6], [7], [8], [9], [10], [11], [12], [13], [14]. Significant crosstalk and redundancy also occur between the ATR, ATM and DNA-PKcs pathways in order to maintain genomic stability in cells [15], [16], [17], [18].
    Methods
    Results
    Discussion Overall prognosis for advanced ovarian cancer remains poor. Resistance to platinum based chemotherapy adversely impacts patient outcome [4], [5]. DNA damage induced by platinum chemotherapy is, to a large extent, processed by the DNA damage signalling and repair machinery in cells. Up-regulation of DNA damage signalling and repair pathways may be an important cause of therapeutic resistance in ovarian cancer. ATM, DNA-PKcs and ATR are key proteins involved in DNA repair in response to DNA damaging chemotherapy [6], [7], [8], [9], [10], [11], [12], [13], [14]. Altered expression of ATM, DNA-PKcs and ATR may have prognostic and predictive significances in ovarian cancer. In the current study we have provided evidence that ATM, DNA-PKcs and ATR are promising biomarkers in ovarian cancer. We found that high ATM expression was associated with serous cystadenocarcinomas, poor response to chemotherapy and platinum resistance. High DNA-PKcs expression was associated with serous cystadenocarcinomas, advanced stage and high grade tumours. In univariate analysis, high ATM, high DNA-PKcs and high ATR expression are associated with poor ovarian cancer specific survival (OCSS) and progression free survival (PFS). Taken together, ATM+/DNA-PKcs+/ATR+ tumours had the worst survival compared to ATM-/DNA-PK-/ATR- tumours. In a separate cohort, the adverse prognostic significance was also observed at the mRNA level for ATM and DNA-PKcs implying that high protein levels may be related to high ATM and DNA-PKcs mRNA levels in tumours. For ATR, mRNA levels were not significant implying that post-transcriptional mechanisms may be operating in certain tumours to increase ATR protein levels. In fact, pre-clinical evidence that such a mechanism may be operating to control ATR protein levels has recently been demonstrated [24]. A limitation in the current study is that we were unable to compare protein and mRNA expressions in the same cohort. Nevertheless, the clinical data presented here does suggest that high ATM/DNA-PKcs/ATR expressing tumours may be less sensitive to chemotherapy. The data is entirely consistent with pre-clinical studies demonstrating an essential role for ATM, DNA-PKcs and ATR in determining platinum sensitivity in cancer cell line models. Depletion or inhibition by small molecule inhibitors has been shown to result in platinum sensitivity [25], [26], [27], [28], [29]. In multivariate Cox model for OCSS, high DNA-PKcs and high ATR expression was independently associated with poor survival providing further evidence for prognostic and predictive significance in ovarian cancer. However, as discussed previously, the data is retrospective and is in need of prospective validation in larger multicentre studies. Another limitation to the study is that we have investigated ATM, DNA-PKcs and ATR expressions only in static states. Moreover, post-translational modification of downstream proteins such as phosphorylation of Chk1 and Chk2 are essential for functional capacity of pathways. Analyses of expression of phosphorylated Chk1, phosphorylated Chk2 and autophosphorylated forms for ATM, DNA-PKcs and ATR may provide further insights into the clinicopathological significance of the DNA damage signalling pathways in ovarian cancers.