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Molecular discovery suggests new strategy to fight cancer drug resistance
Date:6/20/2010

BOSTONScientists at Dana-Farber Cancer Institute have found a way to disable a common protein that often thwarts chemotherapy treatment of several major forms of cancer.

The researchers discovered, surprisingly, that they could exploit a small portion of this anti-death protein, called MCL-1, to make a molecular tool that specifically blocked MCL-1's "pro-survival" action, allowing standard cancer drugs to kill the tumor cells by apoptosis, or programmed cell death.

"We think this is a very important step toward developing an inhibitor of MCL-1, which is emerging as a critical survival factor in a broad range of human cancers, including leukemia, lymphoma, multiple myeloma, melanoma, and poor-prognosis breast cancer to name just a few," said Loren Walensky, MD, PhD, a pediatric oncologist and chemical biologist at Dana-Farber and Children's Hospital Boston.

He is the senior author of the report being published June 20 on the website of Nature Chemical Biology. The first author is Michelle Stewart, a graduate student in the Walensky lab.

The researchers showed in lab experiments that combining the MCL-1 inhibitor with a class of conventional agents that can be rendered ineffective by MCL-1 resensitized the cancer cells to the drugs. The MCL-blocking compound is now being advanced to testing in animal models.

MCL-1 belongs to the BCL-2 family, a yin-and-yang collection of proteins that control the process of apoptosis, which is designed to rid the body of unneeded cells during embryonic development or cells that have become damaged or cancerous. The "pro-death" BCL-2 members form a pathway that triggers cellular self-destruction, while "pro-survival" members of which MCL-1 is one establish blockades in the death pathway, often by binding to pro-death proteins and disabling them.

Cancer cells exploit the survival pathway by over-expressing anti-apoptotic proteins such as MCL-1, which makes chemothe
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Contact: Bill Schaller
william_schaller@dfci.harvard.edu
617-632-5357
Dana-Farber Cancer Institute
Source:Eurekalert  

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