Multi-Metric Synergy Analysis of WEE1 Inhibitor Adavosertib with DNA-Damaging Drugs Identifies Candidate Therapeutic Windows in a TNBC Cell Line Model

Triple-negative breast cancer (TNBC) lacks targetable receptors and relies on the WEE1 kinase-mediated G2/M checkpoint for survival, positioning WEE1 inhibition as a rational strategy to sensitize TNBC to DNA-damaging treatments (DNAdt). This study provides a multi-metric pharmacodynamic characterization of adavosertib combined with DNAdt (doxorubicin, cisplatin, and 5-FU) in TNBC MDA-MB-231 and non-transformed MCF10-A mammary epithelial cells. Dose-response surfaces analyzed via SynergyFinder yielded multi-model, multi-metric ZIP synergy scores (ZSS), combination sensitivity scores (CSS), and synergy score density (SSD). The apparent interaction potential (ψ, psi), an exploratory tripartite parameter integrating ZSS, SSD, and CSS (range −1 to +1), was introduced for systematic characterization and prioritization. With the ZIP model, MDA-MB-231 combinations exhibited moderate synergistic ψ (0.37-0.42); MCF10-A showed moderate antagonistic ψ for cisplatin and 5-FU (−0.31 to −0.37). At the selected ZIP thresholds (≥ 5 synergy; ≤ −5 antagonism), 5-FU-adavosertib in MDA-MB-231 and doxorubicin-adavosertib in MCF10-A exhibited dual synergistic-antagonistic behavior. Fifty exclusive synergistic pairs (ZIP score ≥ 5), absent from MCF10-A, yielded three drug-specific candidate therapeutic windows based on SS and ψ (5-FU-adavosertib), CSS (doxorubicin-adavosertib), and multi-metric consensus rank (cisplatin-adavosertib). Mechanistic characterization was consistent with pCDC2 (Tyr15) abrogation and DNAdt-specific γH2AX induction within the TNBC-selective therapeutic window. These findings provide a multi-metric pharmacodynamic framework for exploring adavosertib-DNAdt combinations as candidates for further translational evaluation in TNBC cell line models.