Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

1136 Chapter 20: Cancer
(A)
ONCOGENIC KINASE ACTIVE
(B)
target
protein
ATP
activating
phosphate
P
signal for cell
proliferation
and survival
LEUKEMIA
hyperactive
oncogenic kinase
ADP
ONCOGENIC KINASE BLOCKED WITH GLEEVEC
target
protein
no signal
NO LEUKEMIA
(C)
H
H
N
N
N
N
N
Gleevec
inactivated
oncogenic kinase
N
O
N
Gleevec
Figure 20–43 How imatinib (Gleevec) blocks the activity of Bcr-Abl protein and halts chronic myelogenous leukemia.
(A) Imatinib sits in the ATP-binding pocket of the tyrosine kinase domain of Bcr-Abl and thereby prevents Bcr-Abl from
transferring a phosphate group from ATP onto a tyrosine residue in a substrate protein. This blocks transmission of a signal for
cell proliferation and survival. (B) The structure of the complex of imatinib (solid blue object) with the tyrosine kinase domain of
the Abl protein (ribbon diagram), as determined by x-ray crystallography. (C) The chemical structure of the drug. It can be given
by mouth; it has side effects, but they are usually quite tolerable. (B, from T. Schindler et al., Science 289:1938–1942, 2000.
With permission from AAAS.)
Results are not so good for those patients who have already progressed to the
more acute phase of myeloid leukemia, known as blast crisis, where genetic instability
has set in and the march of the disease is far more rapid. These patients show
a response at first and then relapse because the cancer cells develop a resistance
to imatinib. This resistance is usually associated with secondary mutations in the
part of the Bcr-Abl gene that encodes the kinase domain, disrupting the ability
of imatinib to bind to Bcr-Abl kinase. Second-generation inhibitors that function
effectively against a whole range of imatinib-resistant mutants have now been
developed. By combining one or more of these new inhibitors with imatinib as
the initial therapy (see below), it seems that CML—at least in the chronic (early)
stage—may be on its way to becoming a curable disease.
Despite the complications with resistance, the extraordinary success of imatinib
is enough to drive home an important principle: once we understand pre-
MBoC6 m20.52/20.43
cisely what genetic lesions have occurred in a cancer, we can begin to design effective
rational methods to treat it. This success story has fueled efforts to identify
small-molecule inhibitors for other oncogenic protein kinases and to use them
to attack the appropriate cancer cells. Increasing numbers are being developed.
These include molecules that target the EGF receptor and are currently approved
for the treatment of some lung cancers, as well as drugs that specifically target the
B-Raf oncoprotein in melanomas.
Protein kinases have been relatively easy to inhibit with small molecules
like imatinib, and many kinase inhibitors are being produced by pharmaceutical
companies in the hope that they can be effective as drugs for some forms of
cancer. Many cancers lack an oncogenic mutation in a protein kinase. But most
tumors contain inappropriately activated signaling pathways, for which a target