Serum APE1 as a predictive marker for platinum-based chemotherapy of non-small cell lung cancer patients

Abstract

PurposeTo define the role of the DNA repair protein apurinic/apyrimidinic endonuclease 1 (APE1) in predicting the prognosis and chemotherapeutic response of non-small cell lung cancer patients receiving platinum-containing chemotherapy.ResultsOur investigations found that serum APE1 level was significantly elevated in 229 of 412 NSCLC patients and correlated with its level in tissue (r2 = 0.639, p < 0.001). The elevated APE1 level in both tissue and serum of patients prior to chemotherapy was associated with worse progression-free survival (HR: 2.165, p < 0.001, HR: 1.421, p = 0.012), but not with overall survival. After 6 cycles of chemotherapy, a low APE1 serum level was associated with better overall survival (HR: 0.497, p = 0.010).Experimental DesignWe measured APE1 protein levels in biopsy tissue from 172 NSCLC patients and sera of 412 NSCLC patients receiving platinum-based chemotherapy by immunohistochemistry and a newly established sensitive and specific enzyme-linked immunosorbent assay, respectively. APE1 levels in sera of 523 healthy donors were also determined as control.ConclusionsOur studies indicate that APE1 is a biomarker for predicting prognosis and therapeutic efficacy in NSCLC. The chemotherapy-naïve serum APE1 level, which correlated with its tissue level inversely associated with progression-free survival of platinum-containing doublet chemotherapy, whereas post-treatment serum APE1 level was inversely associated with overall survival.

The extracellular role of DNA damage repair protein APE1 in regulation of IL-6 expression

“…Thus under certain conditions such as inflammatory response or tumorigenic condition induce secretion of APE1 from cells. Consistent with this idea, elevated levels of serum APE1 and its auto-antibody, have been found to be present in lung cancer patients' [54, 55] The presence of the extracellular APE1, therefore, questions the biological significance of this secretion. Moreover, a recent study has shown that extracellularly secreted APE1/Ref-1 triggers apoptosis in triple-negative breast cancer cells [24].…”

“…Indeed, auto-antibodies against APE1 have been identified in systemic lupus erythematous patients [66]. Recently, the identification of serum APE1 and its auto-antibody, and its differential presence among normal controls and lung cancer patients further indicate APE1 as an autoimmune antigen [54, 55]. Our finding of the secretory APE1 from monocytes upon inflammatory challenges, and its role as a regulator of IL-6 mediated cellular responses marks this protein as a target for therapeutic intervention.…”

The regulatory role of APE1 in epithelial‐to‐mesenchymal transition and in determining EGFR‐TKI responsiveness in non‐small‐cell lung cancer

“…We recently discovered that APE1 protein is also present in human serum and, more importantly, is elevated in NSCLC patients, and correlates with platinum‐containing chemotherapy responses. When tracing serum APE1 throughout treatment, APE1 levels change during chemotherapy and reflect therapeutic outcomes . Based on this observation, we initiated a trial to monitor changes in serum APE1 levels during EGFR‐TKI treatment.…”

“…When tracing serum APE1 throughout treatment, APE1 levels change during chemotherapy and reflect therapeutic outcomes. 25 Based on this observation, we initiated a trial to monitor changes in serum APE1 levels during EGFR-TKI treatment. If a correlation between serum APE1 level and EGFR-TKI response can be observed prior to the actual imaging progression, we could predict resistance events and prophylactically add APE1 inhibitors or other possible interventions by real-time monitoring.…”

Apurinic/apyrimidinic endonuclease 1 (APE1/Ref‐1) overexpression is an independent prognostic marker in prostate cancer without TMPRSS2:ERG fusion

“…[5][6][7][8][9][10][11] In normal tissues, APE1 becomes upregulated in response to oxidative stress. 12 Upregulation of APE1 has been reported from a multitude of human cancer types, including hepatocellular carcinoma, osteosarcoma, breast, lung, ovarian, colorectal, and bilio-pancreatic cancer [12][13][14][15][16] and has been linked to adverse tumor phenotype and poor patient prognosis in some of them. [17][18][19][20] Consequently, APE1 has recently gained interest as an emerging anti-cancer drug target.…”