While outcomes have substantially improved for many types of cancer, endometrial cancer incidence and deaths are on the rise, with the five year survival rate worse today than three decades ago. Inadequate sensitivity to chemotherapy is a primary cause of therapeutic failure. Sensitivity to chemotherapy depends upon the ability to enhance the number of cells in vulnerable periods of the cell cycle: taxanes are effective for cells in M, and platinum-based compounds and anthracyclines work primarily in S. The ability of cells to activate cell cycle checkpoints prevents progression into vulnerable phases of the cell cycle, leading to chemoresistance. Mutations in TP53, KRAS, PTEN, genes encoding PI3Kinase, and growth factor receptors such as FGFR2 predominate in endometrial cancer, altering master regulators of cell cycle checkpoints in unique and predictable ways and de-sensitizing cells to chemotherapy. Our objective was to determine whether molecular inhibitors of key master regulators of cell cycle checkpoints, chosen based upon the knowledge of the tumor phenotype, synergize with chemotherapy and create synthetic lethality. Studies utilized well-defined in vitro cell models of endometrial cancers with known phenotypes / mutations. Our data demonstrate that endometrial cancer cells with inactivated p53 relied on the p38MAPK pathway to maintain the G2/M checkpoint. As such, these p53-null tumors were exquisitely sensitive to treatments that abrogate the G2/M checkpoint, including the combination of paclitaxel with inhibitors of receptor tyrosine kinases (RTK), p38MAPK, or downstream Wee-1. For example, treatment of p53-null endometrial cancer cells with a molecular inhibitor against EGFR lowered the IC50 of paclitaxel by 10-fold, with a combination index of 0.25 indicative of profound synergy. Studies in endometrial cancer cells with p53 gain-of-function mutations, which occur in ~15-20% of serous endometrial tumors, revealed the critical nature of overcoming the G2/M checkpoint. Cells with gain-of-function p53 were highly resistant to the combinatorial approach of paclitaxel and RTK inhibitor, most likely due to maintenance of the G2/M checkpoint. Knockdown of the gain-of-function p53 restored sensitivity to the paclitaxel and RTK inhibitor combination. However, combination of a Wee-1 inhibitor, which targets the G2/M checkpoint downstream of constitutive p38MAPK activation, with paclitaxel created synthetic lethality in all tested cell lines regardless of p53 status. Therefore, our data reveal strategies to overcome the impact of driver mutations by combining standard chemotherapy with appropriate molecular inhibitors which can enhance cell sensitivity, a concept we term molecularly enhanced chemotherapy. Ongoing studies are examining the effect of driver mutations on master regulators of checkpoint maintenance as predictors of chemoresistance in specimens from the completed clinical trial, GOG 177, which compared a therapeutic regiment of cisplatin + adriamycin vs cisplatin + adriamycin + paclitaxel in patients with advanced or recurrent endometrial cancer. These findings will serve as the platform for the rational development of novel therapeutic strategies for endometrial cancer that have a significant potential for early translation to the clinic.
Citation Format: Kristina Thiel, Xiangbing Meng, Henry Reyes, Kimberly Leslie. p53 status directs choice of molecularly enhanced chemotherapy to achieve synthetic lethality in endometrial cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B06.
- ©2013 American Association for Cancer Research.