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Drug sensitivity may be restored by 'drug holiday' or by inhibiting emergence of resistant cells

-- Jeff Muise

Wednesday, April 21, 2010 (Last Updated: 04/22/2010)

WEDNESDAY, April 21 (HealthDay News) -- The development of chemotherapy resistance in some cancers results from the emergence of small transient populations of drug-resistant cells, which can resolve or be actively inhibited to restore drug sensitivity, according to a study in the April 2 issue of Cell.

Sreenath V. Sharma, Ph.D., of the Massachusetts General Hospital Cancer Center in Charlestown, and colleagues treated a non-small cell lung cancer cell line with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib, to which the parent tumor was sensitive. The researchers found certain cancer cells survived treatment at as much as 100 times the usual lethal concentration. A gene expression analysis of the parent and resistant cells was performed to investigate the mechanism of resistance.

In the resistant cells, the analysis identified elevated expression of KDM5A/RBP2/Jarid1A, a gene for a chromatin-modifying enzyme associated with histone deacetylases (HDACs) expression. By inhibiting the gene using RNA interference, the researchers could significantly reduce the cell population with EGFR TKI retreatment, indicating restored drug sensitivity. The researchers tested 13 agents and found that only AEW541, a selective inhibitor of the insulin-like growth factor 1 receptor kinase, prevented the emergence of new resistant cells.

"Reversible drug tolerance may account for accumulating clinical reports demonstrating that cancer patients treated with a variety of anticancer drugs can be successfully retreated with the same drug after a 'drug holiday.' The detection of a distinct chromatin state in drug-tolerant cancer cells and consequent hypersensitivity to HDAC inhibitors potentially yields a therapeutic opportunity to prevent the development of stable drug resistance," the authors write.

Abstract
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Specialties Hematology & Oncology
OBGYN & Women's Health
Pathology
Family Practice
Internal Medicine

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