Abstract 2969: A Wee1 kinase inhibitor, MK-1775, sensitizes cervical carcinoma cell lines to cisplatin and topotecan

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The Wee1 tyrosine kinase plays a key role in checkpoint arrest by phosphorylating and inhibiting cyclin-dependent kinases 1 and 2, two CDKs that drive S-phase and G2- to M-phase transitions, respectively. Interfering with Wee1 leads to elevated CDK1 and 2 activity, which in turn overcomes checkpoint arrest and causes cells to progress through the cell cycle in the presence of DNA damage. Wee1 inhibitors are therefore expected to sensitize cancer cells to DNA damaging chemotherapeutics. In particular, p53-deficient cells are postulated to be particularly sensitive to Wee1 inhibition because they lack a G1-checkpoint and rely more on S- and G2-phase checkpoints where Wee1 activity is critical. The p53 pathway is frequently inactivated in cervical carcinoma either through TP53 mutation or through functional inactivation by Human PapillomaVirus (HPV) gene products. We thus investigated the capability of MK-1775, a selective and potent inhibitor of Wee1, to sensitize cervical cancer cell lines to cisplatin and topotecan. We have evaluated the potential of the Wee1 inhibitor MK-1775 to sensitize cervical cancer cells to standard-of-care treatments both in vitro and in vivo. Using a panel of cervical cancer cell lines, we demonstrated that MK-1775 at clinically relevant concentrations potentiates the cytotoxic activity of cisplatin and topotecan in vitro as indicated by the average 3-fold and 2-fold shift in the CC50s for cisplatin and topotecan, respectively. Chemosenstization was observed in both HPV-negative/p53 mutant and HPV-positive p53/wild-type cervical cancer cell lines. Finally, we have demonstrated that MK-1775 significantly increases the in vivo efficacy of a cisplatin-topotecan combination therapy in xenograft models of HPV+ cervical carcinoma. Based on these data, MK-1775 is currently undergoing clinical evaluation in a phase 1b/2 trial in platinum combination for the treatment of cervical carcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2969. doi:10.1158/1538-7445.AM2011-2969