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

CANCER PREVENTION AND TREATMENT: PRESENT AND FUTURE
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PARP inhibition provides an example of the type of rational, highly selective
approach to cancer therapy that is beginning to be possible. Along with other new
treatments to be discussed below, it raises high hopes for treating many other
cancers.
Small Molecules Can Be Designed to Inhibit Specific Oncogenic
Proteins
An obvious tactic for treating cancer is to attack a tumor expressing an oncogene
with a drug designed to specifically block the function of the protein that the
oncogene produces. But how can such a treatment avoid hurting the normal cells
that depend on the function of the proto-oncogene from which the oncogene has
evolved, and why should the drug kill the cancer cells, rather than simply calm
them down? One answer may lie in the phenomenon of oncogene dependence.
Once a cancer cell has undergone an oncogenic mutation, it will often undergo
further mutations, epigenetic changes, or physiological adaptations that make it
reliant on the hyperactivity of the initial oncogene, just as drug addicts become
reliant on high doses of their drug. Blocking the activity of the oncogenic protein
may then kill the cancer cell without significantly harming its normal neighbors.
Some remarkable successes have been achieved in this way.
As we saw earlier, chronic myelogenous leukemia (CML) is usually associated
with a particular chromosomal translocation, visible as the Philadelphia chromosome
(see Figure 20–5). This results from chromosome breakage and rejoining
at the sites of two specific genes, Abl and Bcr. The fusion of these genes creates
a hybrid gene, called Bcr-Abl, that codes for a chimeric protein consisting of the
N-terminal fragment of Bcr fused to the C-terminal portion of Abl (Figure 20–42).
Abl is a tyrosine kinase involved in cell signaling. The substitution of the Bcr fragment
for the normal N-terminus of Abl makes it hyperactive, so that it stimulates
inappropriate proliferation of the hemopoietic precursor cells that contain it and
prevents these cells from dying by apoptosis—which many of them would normally
do. As a result, excessive numbers of white blood cells accumulate in the
bloodstream, producing CML.
The chimeric Bcr-Abl protein is an obvious target for therapeutic attack.
Searches for synthetic drug molecules that can inhibit the activity of tyrosine
kinases discovered one, called imatinib (trade name Gleevec®), that blocks Bcr-
Abl (Figure 20–43). When the drug was first given to patients with CML, nearly
all of them showed a dramatic response, with an apparent disappearance of the
cells carrying the Philadelphia chromosome in over 80% of patients. The response
appears relatively durable: after years of continuous treatment, many patients
have not progressed to later stages of the disease—although imatinib-resistant
cancers emerge with a probability of about 5% per year during the early years.
Bcr gene on chromosome 22
5′ 3′
Abl gene on chromosome 9
5′ 3′
breakpoint
breakpoint
TRANSLOCATION
5′ 3′
fused Bcr-Abl gene
TRANSCRIPTION
5′ 3′
AAA fused Bcr-Abl mRNA
TRANSLATION
Bcr-Abl fusion protein
Figure 20–42 The conversion of the
Abl proto-oncogene into an oncogene
in patients with chronic myelogenous
leukemia. The chromosome translocation
responsible joins the Bcr gene on
chromosome 22 to the Abl gene from
chromosome 9, thereby generating a
Philadelphia chromosome (see Figure
20–5). The resulting fusion protein has the
N-terminus of the Bcr protein joined to
the C-terminus of the Abl tyrosine protein
kinase; in consequence, the Abl kinase
domain becomes inappropriately active,
driving excessive proliferation of a clone of
hemopoietic cells in the bone marrow.