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Blocking telomerase kills cancer cells but provokes resistance, progression
Date:2/21/2012

HOUSTON - Inhibiting telomerase, an enzyme that rescues malignant cells from destruction by extending the protective caps on the ends of chromosomes, kills tumor cells but also triggers resistance pathways that allow cancer to survive and spread, scientists report in the Feb. 17 issue of Cell.

"Telomerase is overexpressed in many advanced cancers, but assessing its potential as a therapeutic target requires us to understand what it does and how it does it," said senior author Ronald DePinho, M.D., president of The University of Texas MD Anderson Cancer Center.

"We exploited the experimental merits of mice to model and study more precisely telomere crisis, telomerase reactivation and telomerase extinction in cancer development, progression and treatment," DePinho said. "This elegant model exposed two mechanisms, including one unexpected metabolic pathway, used by cancer cells to adapt to loss of telomerase.

"These findings allow us to anticipate how tumor cells might respond to telomerase inhibition and highlight the need to develop drug combinations that target telomerase and these adaptive resistance mechanisms," DePinho said.

Researchers evaluated telomerase as a therapeutic target in experiments that originated in DePinho's lab at the Dana-Farber Cancer Institute in Boston. He became MD Anderson's fourth full-time president in September.

Telomerase activity is low or absent in normal cells, which have segments of repeat nucleotides called telomeres at the ends of their chromosomes that protect DNA stability during cell division, said first author Jian Hu, Ph.D., an instructor in MD Anderson's Department of Cancer Biology.

With each division the telomeres shorten, leading eventually to genomic instability and cell death, a period termed "telomere crisis," Hu said. In cancer, telomerase becomes active during telomere crisis and rescues the genomically abnormal cells by lengthening telomeres.


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Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert

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