The human body does a great job of generating new cells to
replace dead ones but it is not perfect. Cells need to communicate with or
signal to each other to decide when to generate new cells. Communication or
signaling errors in cells lead to uncontrolled cell growth and are the basis of
many cancers.
At The University of Texas Health Science Center at Houston
(UTHealth) Medical
School, scientists have
made a key discovery in cell signaling that is relevant to the fight against
melanoma skin cancer and certain other fast-spreading tumors.
The scientists report that they have discovered why a class
of drug called BRaf inhibitors that are widely used to treat melanomas do not
always work and most importantly how these drugs may potentially accelerate
cancer growth in certain patients. Melanoma, according to the American Cancer
Society, accounts for almost 9,000
deaths each year. The scientists’ research was published online ahead
of the June 5 print issue of Current Biology, which is published by Cell Press.
“This information may aid the development of more effective
anti-cancer drugs and better inform the choice of new combinations of drugs,”
said John
Hancock, M.B, B.Chir, Ph.D., the study’s senior author, John S. Dunn
Distinguished University Chair in Physiology and Medicine, chairman of the
Department of Integrative Biology and Pharmacology and interim director of the
Brown Foundation Institute of Molecular Medicine for the Prevention of Human
Diseases at the UTHealth Medical School.
Growth signals are transmitted from a cell’s surface to the
nucleus by a chain of proteins that form a signaling pathway. The command
for cells to divide to generate new cells is relayed by a chain of four
proteins (Ras ? BRaf ? MEK ? ERK). All cells have this pathway and it does an
effective job of generating new cells most of time.
Problems happen when a mutation occurs in one of the first
two proteins in the chain – both of which lock the signaling pathway in the
“on” position. The good news is that doctors have drugs that block signaling
from the second protein known as BRaf. These are the BRaf inhibitors, which are
successful at treating melanomas with mutant BRaf
proteins.
The not-so-good news is that doctors cannot block the signal
from the first protein called Ras. Researchers therefore studied in vivo what
happens when BRaf inhibitors are applied to human cancer tissues with Ras
mutations.
“Surprisingly recent studies found that BRaf inhibitors do
not block signaling in melanoma cells with Ras mutations. In fact, the drugs actually
enhance the abnormal signaling activity. Our work now describes the mechanism
for this seemingly paradoxical enhanced signaling activity,” said Kwang-jin
Cho, Ph.D., the study’s lead author and research fellow at the UTHealth Medical School.
Most melanomas isolated from patients turn out to have
either a BRaf or Ras mutation but rarely have both. Ras mutations cause an
otherwise normal BRaf protein to stay switched on.
“Our study also emphasizes the importance of genetic testing
of melanomas before using BRaf inhibitors. Our study may also help design a
better drug,” Cho said.
The study, which is titled “Raf inhibitors target Ras
spatiotemporal dynamics,” was supported by the Cancer Prevention & Research Institute
of Texas.
Hancock and Cho’s co-authors from the UTHealth
Medical School
are: Jin-Hee Park, senior research assistant;
Sravanthi Chigurupati, senior research assistant; Dharini van der Hoeven,
Ph.D., research fellow; and Sarah J. Plowman, Ph.D., assistant professor.
Other collaborators include: Rinshi S. Kasai, Ph.D., and
Akihiro Kusumi, Ph.D., Kyoto University, Japan; and Sonja J. Heidorn, Ph.D., and Richard
Marais, Ph.D., Institute for Cancer Research, London.
