Signaling Protein For Multiple Myeloma Identified, Findings May
Result In New Therapeutic Target
Sept. 12, 2007
Researchers at Emory University's Winship Cancer Institute are the
first to discover a mechanism that plays a critical role in the
multiple myeloma cell cycle and survival. Their research may result
in identification of a new therapeutic target for treating multiple
myeloma.
The results of the study appear in the September issue of Cancer
Cell. Jing Chen, PhD, assistant professor of hematology and oncology
at Emory Winship and a Georgia Cancer Coalition Distinguished Cancer
Scholar, is senior author on the paper. Sumin Kang, PhD, a
postdoctoral fellow at Emory Winship, is the paper's first author.
Multiple Myeloma is among the most common hematologic malignancies in
patients over 65. About15 percent of multiple myeloma patients harbor
a genetic abnormality called "t(4;14) chromosomal translocation" that
causes over-expression of a tyrosine kinase called fibroblast growth
factor receptor 3 (FGFR3).
Tyrosine kinases are molecules that act as biological switches inside
cells, regulating processes including cell division and growth.
Abnormal kinases have been identified as a driving force in many
forms of cancer.
"We are interested in how FGFR3 mediates transforming signals," says
Dr. Chen. "We wanted to know which protein factors in cells are
activated by FGFR3 and then transform normal cells to highly
malignant cells. We identified Ribosomal S6 kinase 2 (RSK2), which is
a protein factor that mediates signaling in cells as critical in
downstream signaling of FGFR3 in myeloma cells."
Dr. Chen and his colleagues are the first to discover a mechanism
to "turn-on" RSK2 by FGFR3. FGFR3 impacts downstream proteins through
phosphorylation at special "tyrosine" sites.
"We found that FGFR3 directly phosphorylates RSK2, which is a
critical step in the process to activate (turn-on) RSK2," says Dr.
Chen.
The researchers observed that elimination of RSK2 proteins or
shutting down RSK2 activity blocks FGFR3 transformation signaling in
myeloma cells. This means FGFR3 requires RSK2 to transform normal
cells.
"This is a beautiful model," says Dr. Chen. "We are able to mark the
connection between the oncogenic FGFR3 and its downstream protein
kinase RSK2, which plays a critical role in regulation of cell cycle
and survival. These findings extend our understanding of pathogenesis
of multiple myeloma in a signaling basis."
Collaborators on the project include Roberto Polakiewicz, PhD, and
Ting-Lei Gu, PhD, both of Cell Signaling Technologies (CST),
developers of the "PhosphoScan" technology, which enables
investigators to identify hundreds to thousands of phosphorylated
sequences and observe the global state of protein tyrosine
phosphorylation in cells and tissues.
"Using this technology," says Dr. Chen, "we identified RSK2 as a
critical downstream signaling protein effector of FGFR3 in myeloma
cells." Other authors include researchers from the University of
California at San Francisco, Harvard Medical School, Mayo Clinic and
Novartis Pharma AG.
Dr. Chen and his colleagues also tested a drug called fmk that was
designed by co-author Jack Taunton, PhD, at UCSF to specifically
target RSK2 in treatment of human malignant myeloma cells from
laboratory culture or primary samples from multiple myeloma patients,
and saw that fmk effectively kills t(4;14) myeloma cells with
abnormal over-expression of FGFR3.
"This study shows the potential utility of drugs that block the
downstream effectors of mutant tyrosine kinases, and that these drugs
are opening more doors to treating hematologic malignancies and
cancers," explains Dr. Chen. In addition to the t(4;14) in multiple
myeloma that is caused by abnormal over-expression of FGFR3,
abnormality of FGFR3 has also been identified in human bladder and
cervical cancers. The findings suggest, the authors write, that
targeting RSK2 with RSK inhibitors such as fmk may be effective in
treating t(4;14) multiple myeloma, as well as other diseases and
cancers where mutant FGFR3 is the culprit.
------------
Article adapted by Medical News Today from original press release.
------------
The research was supported by grants from the National Institutes of
Health, the Leukemia and Lymphoma Society and the Multiple Myeloma
Research Foundation.
About Emory Winship Cancer Institute: As a leader in cancer patient
care and research, Emory University's Winship Cancer Institute (EWCI)
offers new therapies not usually available outside university-
affiliated medical centers, including nearly 150 clinical trials for
all types and stages of cancer. The EWCI serves as the coordinating
center for a vast array of resources in medical, surgical and
radiation oncology, diagnostic imaging, and the subspecialties of
cancer care throughout Emory University -from blood and bone marrow
stem cell transplants to internationally recognized breast
reconstruction. For more information, visit:
http://www.cancer.
Source: Vincent Dollard
Emory University
http://www.medicaln
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