Cdc7 Kinase Is a Predictor of Survival and a Novel Therapeutic Target in Epithelial Ovarian Carcinoma

Abstract

Purpose: There is a lack of prognostic and predictive biomarkers in epithelial ovarian carcinoma, and the targeting of oncogenic signaling pathways has had limited impact on patient survival in this highly heterogeneous disease. The origin licensing machinery, which renders chromosomes competent for DNA replication, acts as a convergence point for upstream signaling pathways. We tested the hypothesis that Cdc7 kinase, a core component of the licensing machinery, is predictive of clinical outcome and may constitute a novel therapeutic target in epithelial ovarian carcinoma. Experimental Design: A total of 143 cases of ovarian cancer and 5 cases of normal ovary were analyzed for Cdc7 protein expression dynamics and clinicopathologic features. To assess the therapeutic potential of Cdc7, expression was down-regulated by RNA interference in SKOV-3 and Caov-3 ovarian cancer cells. Results: Increased Cdc7 protein levels were significantly associated with arrested tumor differentiation (P = 0.004), advanced clinical stage (P = 0.01), genomic instability (P < 0.001), and accelerated cell cycle progression. Multivariate analysis shows that Cdc7 predicts diseasefree survival independent of patient age, tumor grade and stage (hazard ratio, 2.03; confidence interval, 1.53-2.68; P < 0.001), with the hazard ratio for relapse increasing to 10.90 (confidence interval, 4.07-29.17) for the stages 3 to 4/upper Cdc7 tertile group relative to stages 1to 2/lower Cdc7 tertile tumors. In SKOV-3 and Caov-3 cells, Cdc7 siRNA knockdown triggered high levels of apoptosis, whereas untransformed cells arrest in G 1 phase and remain viable. Conclusions: Our findings show that Cdc7 kinase predicts survival and is a potent anticancer target in epithelial ovarian carcinoma, highlighting its potential as a predictor of susceptibility to small molecule kinase inhibitors currently in development.

The cell cycle and cancer

“…The disappointing intent-to-treat analyses of large, conventionally designed trials, such as TACT and tAnGo, suggests that further improvements in adjuvant treatment will require individualized therapeutic decisions [116,117]. Cell cycle phase analysis of breast and ovarian cancers has shown that it is tumours displaying the accelerated cell cycle phenotype that are most likely to show a clinically relevant response to S-or M-phase-directed agents (Table 1, Figure 3B) [3,74,110,111,118]. As non-proliferating cells are radiation-resistant, whereas cycling cells are most sensitive to radiation insult during transit through G 2 and M phase, tumours displaying the accelerated cell cycle phenotype may also represent those that are most radiation-sensitive.…”

“…This would translate into low therapeutic indices often found for conventional chemotherapeutic drugs targeting the cell cycle. However, potent cancer cell-specific killing has been demonstrated in preclinical models after inhibition of origin licensing [125] or, alternatively, origin activation through targeting Cdc7 kinase [111,118,126,127]. Tumour cell specificity is thought to result from transformed cells entering S phase with inadequate numbers of competent origins to complete chromosomal replication.…”

“…For example, increased Cdc7 expression in breast cancer is associated with Her2 and triple-receptor negative subtypes, the accelerated cell cycle phenotype (c), arrested tumour differentiation, genomic instability, increasing NPI score and reduced disease-free survival [111]. Similarly, increased Cdc7 expression has been linked with arrested tumour differentiation, advanced clinical stage, genomic instability, accelerated cell cycle progression and reduced diseasefree survival in ovarian cancer [118]. We postulate that it will be tumours showing the accelerated cell cycle phenotype (c), high Cdc7 levels and harbouring lesions in the origin activation checkpoint axes that are likely to show optimal response to Cdc7 inhibition.…”

Targeting Cell Division Cycle 7 Kinase: A New Approach for Cancer Therapy

“…Overexpression of Cdc7 in ovarian cancer correlates with tumor anaplasia, aneuploidy, and advanced clinical stage. The greatest discriminatory effect of Cdc7 expression was observed for stage 3 and 4 ovarian tumors, which make up the vast majority of epithelial ovarian carcinoma cases (35). Cdc7 and Dbf4 are overexpressed in malignant melanoma compared with benign melanocytic nevi, and Dbf4 overexpression has been associated with lower relapse-free survival (36,37).…”

ATR–Chk1–APC/CCdh1-dependent stabilization of Cdc7–ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress

“…Overexpression of Cdc7-ASK occurs in various types of cancer (Hess et al 1998;Nambiar et al 2007;Bonte et al 2008;Clarke et al 2009;Kulkarni et al 2009) and often correlates with poor prognosis, suggesting that deregulated Cdc7 kinase activity may promote survival of cancer cells and tumor progression. Recently, some small molecule inhibitors of Cdc7 kinase activity have been developed and are being tested in clinical trials as candidate anti-cancer drugs (Ito et al 2008;Montagnoli et al 2008;Vanotti et al 2008;Ermoli et al 2009).…”