ASH Annual Meeting
SAN DIEGO — Absence of the gene cereblon was associated with
resistance to thalidomide and lenalidomide in patients with multiple myeloma,
according to findings presented here.
Keith Stewart, MD, professor of medicine in the Division of
Hematology-Oncology at Mayo Clinic in Scottsdale, Ariz., recalled that
thalidomide (Thalomid, Celgene) was “serendipitously” discovered to
be active in multiple myeloma in 1999.
“Until recently, though, the mechanism of action was completely
unknown,” he said at a press conference. “These drugs do many things,
but how they get there was a black box until recently a group in Japan
discovered that thalidomide had to bind to a protein called cereblon.”
Binding to cereblon was essential for thalidomide to cause the birth
defects that are a hallmark of thalidomide, Stewart said.
“When we saw that, we concluded that this may also explain the
reason this class of drugs kills many cancer cells,” Stewart said.
“They would have to work through this protein cereblon.”
Stewart noted that, in the absence of cereblon, the drugs have no
“Cereblon is required if the patient is going to respond to
thalidomide or lenalidomide,” he said. “Therefore, this could
potentially serve as a biomarker to responsiveness of whether select patients
will respond or not respond to these drugs.”
In the current study, the researchers examined MM cell lines that were
resistant to immune modulator drugs, including lenalidomide (Revlimid, Celgene)
and pomalidomide. When there was minimal or no presence of cereblon, the cells
were resistant to the drugs.
Stewart and colleagues lowered the level of cereblon in five
human-derived MM cell lines. Compared with control cell lines, those with
lowered cereblon became almost completely resistant to lenalidomide. However,
these cell lines were sensitive to other treatments for myeloma, including
melphalan (Alkeran, GlaxoSmithKline), dexamethasone and bortezomib (Velcade,
The DNA of 10 MM patients with immune modulator resistance was analyzed.
The researchers found low levels of cereblon expression in eight of those
patients. However, normal cereblon levels were observed in some of the
“Our data suggest that cereblon is a critical molecule but not the
unique source of drug resistance in this patient population,” Stewart
The data also indicated that interferon regulatory factor 4 is a common
link between immune modulator drugs and cereblon function.
Disclosure: Dr. Stewart reports receiving consulting fees and
honoraria from Celgene, Onyx and Millennium Pharmaceuticals.
It is important for all of us to note that understanding the various
survival pathways that allow the lipid cells to proliferate and grow, and,
similarly, understanding why some of these cells are resistant to our attempts
at therapy, is at the forefront of research at the current time. Dr. Stewart
has provided us with some exciting new insights about understanding resistance.
His findings are also telling us about survival pathways. These findings are
also illustrating what mechanisms are at work in survivors who don’t
respond to our strategies, and providing information about what new agents
might make patients sensitive to these new therapies.
Jane N. Winter, MD
Northwestern University Feinberg School of
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