Reference Detail

Ref Type

Journal Article

PMID

(24381593)

Authors

Meng X, Dizon DS, Yang S, Wang X, Zhu D, Thiel KW, Leslie KK

Title

Strategies for Molecularly Enhanced Chemotherapy to Achieve Synthetic Lethality in Endometrial Tumors with Mutant p53.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Obstetrics and gynecology international	2013		2013	828165	Obstet Gynecol Int

URL

Abstract Text

Serous uterine endometrial carcinomas are aggressive type II cancers with poor outcomes for which new treatment strategies are urgently needed, in particular, strategies that augment sensitivity to established chemotherapy regimens. The tumor suppressor gene TP53 is dysregulated in more than 90% of serous tumors, altering master regulators of the G2/M cell cycle checkpoint in unique and predictable ways and desensitizing cells to chemotherapy. We hypothesized that synthetic lethality can be achieved in endometrial cancer cells with mutant p53 by combining paclitaxel with agents to overcome G2/M arrest and induce mitotic catastrophe. The combination of BIBF1120, an investigational VEGFR, PDGFR, and FGFR multityrosine kinase inhibitor with established anti-angiogenic activity, with paclitaxel abrogated the G2/M checkpoint in p53-null endometrial cancer cells via modulation of G2/M checkpoint regulators followed by induction of mitotic cell death. In endometrial cancer cells harboring an oncogenic gain-of-function p53 mutation, synthetic lethality was created by combining paclitaxel with BIBF1120 and a histone deacetylase inhibitor, which serves to destabilize mutant p53. These cells were also sensitive to an inhibitor of the G2/M kinase Wee1 in combination with paclitaxel. These findings reveal that, in addition to antiangiogenic activity, the angiokinase inhibitor BIBF1120 can be used to restore sensitivity to paclitaxel and induce mitotic cell death in endometrial cancer cells with non-functional p53. These preclinical data serve as a critical platform for the creative design of future clinical trials utilizing molecularly enhanced chemotherapy to achieve synthetic lethality based on the mutational landscape.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References