Identification of a potential chemotherapeutic agent to treat lynch syndrome tumors

Wednesday, September 24, 2014 — Poster Session IV
10:00 a.m. –12:00 p.m.	FAES Academic Center	NHGRI	CANCER-23

* FARE Award Winner

Authors

• Y. Zhang
• J. Fox
• G. Elliot
• G. Rai
• S. Sakamuru
• R. Huang
• M. Xia
• J. Ortega
• H. Park
• D. Maloney
• G. Li
• K. Myung

Abstract

Impairing the cell division of rapidly dividing cancer cells by small molecules has been a primary goal in the development of chemotherapeutic agents. But Lynch Syndrome tumors have proven to be resistant to most conventional chemotherapeutic agents. Here we identified a compound, F as a small molecule that could selectively kill MutSα-deficient cancer cells. F can bind to DNA and induce DNA damage. In MutSα-proficient cells, F also can directly bind to MutSα and induce dissociation of CHK2 from MutSα. ATM then phosphorylated and activated released CHK2 from MutSα and cells arrested in S phase. In addition, F makes MutSα dissociated from chromatin enriched with histone H3 with K36 tri-methylation. In MutSα-deficient cells, F binds to DNA preferentially at mismatched region. Such F-mismatched DNA appears to be targeted by endonucleases and produce double stranded breaks. Due to lack of MutSα, checkpoint process for mismatched DNA cannot be fully activated. Continued replication in the presence of F leads to form high number of DNA double-strand breaks and ultimately results in apoptosis. These data suggest that F may offer an improved treatment option for patients with lynch syndrome tumors.

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