Abstract 3422: Strategies for molecularly enhanced chemotherapy in endometrial tumors with mutant p53 .
Authors: Meng Xiangbing , Yang Shujie , Zhu Danlin , Wang Xinjun , Thiel Kristina W. , Leslie Kimberly K. 
Published: August 2014

Serous uterine endometrial carcinomas are aggressive type II cancers with a poor outcome and for which new treatment strategies are urgently needed, in particular strategies that augment sensitivity to the established chemotherapy regimen of carboplatin and paclitaxel. The tumor suppressor gene TP53 is dysregulated in more than 50% of serous tumors. Distinct p53 mutations have different properties such that some mutations result in expression of a non-functional protein, whereas others alter binding to transcriptional targets to yield a “gain-of-function” (GOF) oncogenic protein. Our previous work revealed that endometrial cancer cells with inactivated p53 but not GOF p53 are exquisitely sensitive to treatments that abrogate the G2/M checkpoint, such as the combination of an EGFR inhibitor and paclitaxel. Since endometrial cancer cells express multiple angiogenic tyrosine kinase receptors, we hypothesized that anti-angiogenic agents also induce G2/M arrest and mitotic catastrophe when combined with paclitaxel in endometrial cancer cells with non-functional p53. This study utilizes BIBF1120, an investigational VEGFR, PDGFR, and FGFR multi-tyrosine kinase inhibitor with established anti-angiogenic activity in the vascular endothelium. Using endometrial cancer cells with either non-functional or GOF mutations in p53, we examined the impact of combining BIBF1120 and paclitaxel on expression of G2/M checkpoint controllers, cell cycle progression, and cell viability. . When combined with paclitaxel, BIBF1120 abrogated the G2/M checkpoint in p53-null endometrial cancer cells but not in cells with p53 GOF mutation. The mechanism of synergy in the p53-null cells included activation of G2/M checkpoint regulators Cdc25C, Wee1, Myt1 and Cdc2, followed by induction of mitotic cell death. Interestingly, paclitaxel-resistant cells with loss of functional p53 retained sensitivity to the BIBF1120 and paclitaxel combination treatment. In endometrial cancer cells with p53 GOF mutation, sensitivity to the paclitaxel and BIBF1120 combination was restored by the histone deacetylase inhibitor (HDAC) LBH589 or Wee-1 inhibitor MK-1775. These findings reveal that, in addition to anti-angiogenic activity, the angiokinase inhibitor BIBF1120 restores sensitivity to paclitaxel and induces mitotic cell death by targeting multiple growth factor receptors expressed in endometrial cancer cells with p53 loss of function mutation. Our data also identify novel strategies for overriding the G2/M checkpoint and achieving chemosensitization in cells with the oncogenic p53 GOF mutation. These preclinical data serve as a critical platform for the creative design of future clinical trials utilizing molecularly enhanced chemotherapy.

Citation Format: Xiangbing Meng, Shujie Yang, Danlin Zhu, Xinjun Wang, Kristina W. Thiel, Kimberly K. Leslie. Strategies for molecularly enhanced chemotherapy in endometrial tumors with mutant p53 . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3422. doi:10.1158/1538-7445.AM2013-3422