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.
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.
Phone: 61-3-9345-2624; Fax: 61-3-9347-0852; E-mail: strasser@wehi.edu.au .
Mark S. Cragg
Southampton University School of Medicine, Southampton General Hospital, Southampton, United Kingdom.
Phone: 44-2380-777222 ext. 8056; Fax: 44-2380-704061; E-mail: msc@soton.ac.uk .
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.
Phone: (507) 284-8950; Fax: (507) 284-3906; Email: kaufmann.scott@mayo.edu .
View the PDF of this article at: https://www.the-jci.org/article.php?id=37553
Journal of Clinical Investigation