Targeting Tumors With B-RAF Mutations: 2 Drugs Are Better Than 1

Main Category: Cancer / Oncology
Also Included In: Dermatology;  Genetics;  Clinical Trials / Drug Trials
Article Date: 24 Oct 2008 - 5:00 PDT

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In a proportion of human solid tumors, in particular melanomas (a form of skin cancer that is often resistant to chemotherapy), inappropriate activation of the MEK/ERK signaling pathway as a result of mutations in the B-RAF gene promotes tumor cell growth and survival. Although MEK inhibitors stop such tumor cells growing, they have a limited ability to kill the tumor cells. Thus, they have had limited success in promoting tumor regression in preclinical and clinical trials. A team of researchers, at The Walter and Eliza Hall Institute of Medical Research, Australia, has now uncovered the molecular reasons why MEK inhibitors have only a limited ability to kill B-RAF mutant tumor cells and identified another class of drugs that when combined with MEK inhibitors cause tumor regression in mice transplanted with human B-RAF mutant tumor cells.

The team, led by Andreas Strasser and Mark Cragg, found that MEK inhibitors were limited in their ability to kill (by a process known as apoptosis) human B-RAF mutant tumor cells in vitro. The small amount of apoptosis they did induce was mediated via upregulation of the protein Bim. However, if the cells were treated with both a MEK inhibitor and ABT-737 (a drug known as a BH3 mimetic) an extensive amount of apoptosis was observed. Further, the combination also caused tumor regression in mice transplanted with human B-RAF mutant tumor cells; the MEK inhibitor stopped the tumor cells growing and ABT-737 induced the cells to undergo apoptosis. The authors therefore suggest that treating individuals with tumors characterized by B-RAF mutations, especially melanomas, with a MEK inhibitor and a BH3 mimetic might provide a powerful antitumor approach.

Scott Kaufmann and colleagues, at the Mayo Clinic, Rochester, go one step further in their accompanying commentary, asking whether combined MEK inhibitor/BH3 mimetic therapy might be effective for individuals with tumors exhibiting excessive activation of the MEK/ERK signaling pathway in the absence of B-RAF mutations.

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TITLE: Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic

AUTHOR CONTACT:
Andreas Strasser
The Walter and Eliza Hall Institute of Medical Research (WEHI), Parkville, Victoria, Australia.
Mark S. Cragg
Southampton University School of Medicine, Southampton General Hospital, Southampton, United Kingdom.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35437

ACCOMPANYING COMMENTARY
TITLE: Anticancer therapy: boosting the bang of Bim

AUTHOR CONTACT:
Scott H. Kaufmann
Mayo Clinic, Rochester, Minnesota, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=37553

Source: Karen Honey
Journal of Clinical Investigation

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