Navigation Links
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 chemotherapy drugs less effective. Developing drugs to specifically target survival proteins like MCL-1 has been challenging, but Walensky has been making progress on that front.

A small, coiled peptide unit called BH3, which is known as the "death domain," is a key interaction point between pro- and anti-apoptotic proteins. Walensky previously showed that an isolated BH3 coiled structure could be reinforced by chemical "staples" and targeted to the BH3-binding domains of BCL-2 survival proteins, causing the cancer cells in which they are overexpressed to self-destruct.

BH3 domains differ in subtle but important ways from one another, like a set of keys for different locks. Walensky said that molecular mimics of these domains are showing great promise in early clinical trials, yet most of these drugs block three or more BCL-2 family proteins, rather than homing in on one specific cancer-causing target. "An ideal pharmacologic toolbox would contain agents that target individual BCL-2 family proteins, subsets, and all members," explained Walensky, who is also an assistant professor of pediatrics at Harvard Medical School.

In the current research, Walensky and Stewart searched through BH3 domains in cells hoping to find one that could bind to MCL-1 but no other protein and serve as a specific inhibitor of this formidable cancer protein. After combing a collection of BH3 domains, it turned out the one they were looking for was right in front of their eyes the BH3 domain of MCL-1 itself.

The helical BH3 domain of MCL-1 is located within a small "pocket" in the protein structure, and acts as a dock to enable binding of other proteins. It is by means of this docking unit that MCL-1 "traps" pro-death proteins and keeps them from triggering apoptosis in cancer cells. The scientists didn't expect to find that MCL-1's own BH3 domain could, when inserted into the pocket, inhibit its own pro-survival behavior.

"When we uncovered nature's solution to selective MCL-1 targeting, we were surprised by the ironic twist," said Stewart.

The Dana-Farber investigators were also able to analyze the three-dimensional structure of the key parts of the MCL-1 docking mechanism and discover why it binds so specifically to its target.

"Our data provide a blueprint for the development of novel therapeutics to reactive apoptosis in diseases driven by pathologic MCL-1-mediated cell survival and chemoresistance," they wrote.


'/>"/>

Contact: Bill Schaller
william_schaller@dfci.harvard.edu
617-632-5357
Dana-Farber Cancer Institute
Source:Eurekalert  

Related biology news :

1. Genetics Society of America to host 2010 Yeast Genetics & Molecular Biology Meeting
2. Molecular methods are not sufficient in systematics and evolution
3. Team led by Scripps Research scientists discovers bodys own molecular protection against arthritis
4. Pitt pharmacologists go on a molecular fishing trip and hook prize catch
5. New tool helps scientists see molecular signals of eye disease before symptoms arise
6. Lollipops and ice fishing: Molecular rulers used to probe nanopores
7. UT Southwestern researchers identify key molecular step to fighting off viruses
8. Scientists sever molecular signals that prolific parasite uses to puppeteer cells
9. Research pinpoints action of protein linked to key molecular switch
10. Identifying molecular targets for diabetes-related ED
11. Molecular study could push back angiosperm origins
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Molecular discovery suggests new strategy to fight cancer drug resistance
(Date:3/7/2017)... Brandwatch , the leading social intelligence company, today ... to uncover insights to support its reporting, help direct future ... UK,s leading youth charity will be using Brandwatch Analytics social listening ... better understanding of the topics and issues that are a priority ... ...
(Date:3/2/2017)... Who risk to be deprived of its imprint in ... https://www.reportbuyer.com/product/4313699/ WILL APPLE AND SAMSUNG CONFRONT EACH ... using capacitive technology represent a fast growing market, especially ... increase of 360% of the number of fingerprint sensor ... market between 2014 and 2017 (source : N+1 Singer, ...
(Date:2/28/2017)...  EyeLock LLC, ein marktführendes Unternehmen im Bereich ... Lösung zur Iris-Erkennung auf der neuesten Mobilplattform ... dem Mobile World Congress 2017 (27. Februar ... 3, Stand 3E10, vorstellen. Der ... – eine Kombination aus Hardware, Software und ...
Breaking Biology News(10 mins):
(Date:3/27/2017)... 2017 Cousins Properties (NYSE: CUZ ) ... companies, has signed a 10-year, approximately 125,000 square-foot lease at ... located in the Westshore submarket of Tampa, FL. ... has chosen Corporate Center for their new location in ... and chief executive officer of Cousins Properties. "Amgen is a ...
(Date:3/27/2017)... MCLEAN, Va. , March 27, 2017  Perthera,s ... Lombardi Cancer Center, Subha Madhavan , Ph.D., will ... 2017 Joint Summits Panels. On Monday, March 27, 2017, ... Precision Oncology Data More Usable for Research and Care" ... Tuesday, March 28, 2017, she will be a participant ...
(Date:3/27/2017)... -- Trovagene, Inc. (NASDAQ: TROV), a precision medicine biotechnology company, ... Welch , will be presenting at this year,s MicroCap ... at the Essex House in New York ... Mark Erlander , Ph.D., will also be available ... The presentation will be webcast live at http://wsw.com/webcast/microcapconf3/trov ...
(Date:3/24/2017)... Md. , March 24, 2017  Infectex Ltd., ... (MBVF), today announced positive results of a Phase 2b-3 ... therapy regimen in patients with multidrug-resistant pulmonary tuberculosis (MDR-TB). ... scientists at Sequella, Inc. ( USA ) ... A total of 140 patients were enrolled in ...
Breaking Biology Technology: