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Purpose To explore the activity of dasatinib alone and in combination with paclitaxel and carboplatin in ovarian cancer cells and to determine if dasatinib activity can be predicted based on evaluation of the SRC pathway. Experimental Design Microarray analysis was performed for IGROV1, OVCAR3, A2780 and SKOV3 ovarian cancer cells and the status of the genomic SRC signature pathway was determined. Cells were treated with carboplatin, paclitaxel and dasatinib individually and in combination. Pre- and post-treatment phospho-SRC (pSRC) and SRC protein expression was determined. Dose-response curves were constructed, and drug interaction was assessed by the Combination Index (CI) method. Results SRC protein expression levels reflected the SRC pathway genomic signature in the cell lines with the lowest (SKOV3) and highest (IGROV1) pathway expression, but not in those with intermediate expression (OVCAR3, A2780). Dasatinib treatment caused loss of pSRC in all cell lines, with 50% growth inhibition for IGROV1 at 70nM, OVCAR3 at 34nM, A2780 at 4.1μM and SKOV3 at 530nM. Dasatinib combined with cytotoxics yielded a synergistic effect (CI=0.46 to 0.79) in all cell lines except SKOV3. Conclusion Dasatinib in combination with standard chemotherapeutic agents appears to interact in a synergistic manner in some ovarian cancer cell lines. Further research is needed to evaluate tumor cell characteristics which predict response to dasatinib.

BACKGROUND Determination of in situ protein levels of ERCC1 with the antibody (8F1) is prognostic of survival in non-small-cell lung cancer (NSCLC). We previously demonstrated that 8F1 recognizes a second nuclear antigen. We identified this antigen and analyzed its value as a biomarker of clinical outcomes. METHODS The second antigen was identified by mass spectrometry. Protein identity and antibody specificity were confirmed through knockdown and overexpression experiments. Immunohistochemistry (IHC) of 187 early stage NSCLC samples and 60 head and neck squamous cell carcinomas (HNSCC) was used to examine the influence of the second antigen on 8F1 immunoreactivity and association with patient outcomes. RESULTS Cholinephosphate citidylyl transferase–α (CCTα, a.k.a. phosphate citidylyl transferase 1 choline alpha (PCYT1A), a phospholipid synthesis enzyme regulated by RAS, is the second antigen of 8F1. In NSCLC, CCTα contributed (rho = 0.38) to 8F1 immunoreactivity. In squamous cell carcinoma of the lung, CCTα was the dominant determinant of 8F1 immunoreactivity, while its contribution in other subtypes of lung cancer was negligible. High expression of CCTα, but not ERCC1, was prognostic of longer disease-free (log-rank p = 0.002), and overall survival (log-rank p = 0.056). Similarly, in HNSCC, CCTα contributed strongly to 8F1 immunoreactivity (rho = 0.74), and high CCTα expression was prognostic of survival (log-rank p = 0.022 for DFS and p = 0.027 for OS). CONCLUSIONS CCTα is the second antigen detected by 8F1. High CCTα expression is prognostic of survival in NSCLC treated by surgery alone and HNSCC. CCTα is a promising biomarker of patient survival and deserves further study.