Targeting DNA Replication before It Starts: Cdc7 as a Therapeutic Target in p53 Mutant Her2 and Triple Negative Breast Ca.

Abstract

Abstract Based on protein expression profiles of core regulatory proteins involved in the G1–S and G2–M phase transitions, we have identified three distinct cell cycle phenotypes in a series of 200 breast cancers: (I) a G0 “out-of-cycle” state (18% of cases); (II) a G1 arrested/delayed state (24% cases); and (III) accelerated S-G2-M phase progression (58% of cases). The accelerated cell cycle progression phenotype had a higher risk of relapse when compared with G0 and G1-delayed/arrested phenotypes (HR=3.90 (1.81-8.4, p<0.001) and was associated with Her2 and triple negative subtypes (p<0.001). High-grade tumours with the G1 delayed/arrested phenotype showed an identical low risk of relapse compared with well-differentiated G0 tumours. In addition to its prognostic significance, the cell cycle phenotype also impacts on individualised therapeutic decisions. It is only patients showing the actively cycling, aggressive cell cycle phenotype that are likely to benefit from conventional chemotherapeutic S- or M-phase-directed agents or from the new generation of targeted cell cycle inhibitors that are now entering clinical trials.The DNA replication initiation factor Cdc7 is an emerging anti-cancer target. Cdc7 inhibition results in an abortive S phase and potent cancer cell killing. Specificity is based on normal cells undergoing a reversible G1 arrest following Cdc7 inhibition due to activation of a novel cell cycle checkpoint that is lost or impaired in cancer cells. Our analysis of the molecular circuitry underlying this replication origin activation checkpoint reveals that G1 arrest is dependent on three non-redundant checkpoint axes coordinated through the Forkhead transcription factor FoxO3a and p53. We show that only breast cancers displaying the accelerated cell cycle phenotype express elevated Cdc7 levels and are therefore highly represented in p53 mutant Her2-subtype and triple negative tumours. Breast cancers of the luminal subtype expressing low levels of Cdc7 undergo a cytostatic G1 arrest after Cdc7 inhibition due to their p53 wild type status, a checkpoint response mimicking untransformed cells. In contrast Her2 and triple negative tumours show a marked response to Cdc7 inhibitors with potent cancer-cell-specific killing as a result of (i) overexpression of the target protein and (ii) impairment of the origin activation checkpoint due to p53 lesions. Thus integrating cancer cell cycle phenotypic data with a molecular analysis of the origin activation checkpoint serves as a predictor of response to pharmacological Cdc7 inhibitors. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2148.