Another Look at Imatinib Mesylate

Article (PDF Available)inNew England Journal of Medicine 355(23):2481-2 · January 2007with30 Reads
DOI: 10.1056/NEJMcibr065325 · Source: PubMed
n engl j med 355;23 december 7, 2006
clinical implications of basic r esearch
The new england journal of medicine
Genetic abnormalities that occur during neo-
plastic transformation can cause the dysregula-
tion of protein kinases — a critical event in tu-
morigenesis. The inhibition of protein kinases is
one of the most impressive new approaches to tar-
geted cancer therapy. Imatinib mesylate (Gleevec,
Novartis; formerly known as STI571) was one of
the first selective protein kinase inhibitors devel-
oped for the treatment of chronic myelogenous
leukemia (CML). The principal target of imatinib
is BCR-ABL, a fusion protein made up of part of
the breakpoint cluster region (BCR) protein and
part of the tyrosine kinase Abelson murine leu-
kemia (ABL). Imatinib directly binds to the ty-
rosine kinase domain of BCR-ABL and inhibits
its oncogenic activity in CML. (It is also effective
against other tyrosine kinases, including ABL,
KIT, and the platelet-derived growth factor recep-
tor.) This orally administered drug has astonish-
ing efficacy in CML, and clinical studies have not
shown substantial toxic effects. Like the benefits
of cytotoxic chemotherapies and other drug in-
terventions, however, the benefits of treatment
with imatinib are accompanied by adverse ef-
fects that must be managed to facilitate a pa-
tient’s adherence to therapy. Kerkelä et al.
ly described a potential new adverse event: left
ventricular dysfunction and congestive heart fail-
ure in 10 patients treated with imatinib; in these
patients, the ejection fraction (an echocardio-
gram-based measurement of the heart’s pumping
capacity) dropped significantly during therapy.
Kerkelä and colleagues went on to examine the
myocardial histologic features in patients treat-
ed with imatinib and in mice that received clini-
cally relevant doses of this drug. In both cases,
the authors observed membrane whorls in the sar-
coplasmic reticulum and pronounced mitochon-
drial abnormalities of the heart tissue. These are
early signs of toxin-induced myopathies, possibly
due to dysregulated cellular energy homeostasis.
Analyses of isolated cardiomyocytes from mice
that had received imatinib showed low levels of
cellular ATP and the collapse of the mitochondri-
al electrochemical gradient. Kerkelä et al. reported
a modest activation of the apoptotic cascade and
signs of necrosis.
Several conditions of cellular stress, such as
perturbation of calcium homeostasis or the re-
dox status, can lead to the accumulation of mis-
folded proteins in the lumen of the endoplasmic
reticulum, activation of the endoplasmic reticu-
lum stress response, and, consequently, cell death
Fig. 1
). The authors showed that imatinib causes
stress in the endoplasmic reticulum, which in
turn induces cardiomyocyte cell death, suggesting
that the endoplasmic reticulum stress response is
pivotal to the cardiotoxicity associated with ima-
tinib. A previous study
of rat pancreatic cells has
shown that chronic stress is accompanied by an
activation of the Jun N-terminal kinase (JNK) sig-
naling pathways, which leads to cell death. Kerkelä
et al. showed that they could inhibit the imatinib-
induced collapse of the membrane potential in
mitochondria (and thus obviate cell death) by re-
pressing JNK activity. The other effectors of the
stress response, however, remained unchanged,
suggesting that JNK signaling is a consequence
of stress.
Kerkelä and colleagues also tested whether the
observed toxicity is mediated by the inhibition
of known imatinib targets (ABL, KIT, or the plate-
let-derived growth factor receptor). Transfection
with an imatinib-resistant mutant of c-ABL pre-
vented the release of cytochrome c and rescued
cells from imatinib-induced cell death; these find-
ings suggest a novel and vital role of c-ABL in car-
diomyocytes. How ABL fulfills this role is not
clear; perhaps it does so by “turning down the
volume” of the stress effector pathways (
Fig. 1
Targeting the array of kinases in cancer is a
rapidly expanding strategy for developing drugs
for the treatment of cancer. The potential and
specificity of small-molecule compounds direct-
ed against protein kinases are typically evaluat-
ed by means of in vitro testing with kinase pan-
els, which usually include only a subgroup of the
entire human kinase complement (518 enzymes).
Another Look at Imatinib Mesylate
Klaus Strebhardt, Ph.D., and Axel Ullrich, Ph.D.
The New England Journal of Medicine
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Copyright © 2006 Massachusetts Medical Society. All rights reserved.
n engl j med 355;23 december 7, 2006
Secondary modifications and different confor-
mations that affect kinase activity in vivo make
it more difficult, if not impossible, to interpret the
relevance of in vitro assays of function. Proteomic
strategies are therefore attractive. One such strat-
egy provides a “readout” of the entire protein com-
plement of the cell once it has bound a candidate
small-molecule drug. Using this approach, inves-
tigators have shown that selective inhibitors of
receptor tyrosine kinases involved in tumor vas-
cularization also inhibit kinases that mediate oth-
er processes such as control of the cell cycle.
A reevaluation of the considerable data avail-
able for small-molecule inhibitors such as ima-
tinib is necessary. Also underscoring the wisdom
of a reevaluation are the observations that c-ABL
mediates the tumor-suppressor effects of the
EphB4 receptor in breast cancer cells and that
imatinib impairs this cellular defense.
The po-
tential of imatinib to promote epithelial tumor
progression and to induce heart failure should not
be ignored in future clinical trials.
The way in which candidate drugs are tested
before they are assessed in clinical trials also war-
rants reevaluation. In spite of our vastly expand-
ed understanding of the function and physiologi-
cal relevance of every member of the kinase family,
we are just beginning to comprehend their im-
portance at the level of systems biology. It is there-
fore critical that different approaches are strin-
gently and systematically applied in the preclinical
workup of candidate drugs. These approaches in-
clude long-term evaluations of new drugs at clini-
cally relevant doses in valid animal models of
Dr. Ullrich reports receiving lecture fees from Pfizer. No other
potential conflict of interest relevant to this article was reported.
We thank Yves Matthess for his assistance.
From the Department of Obstetrics and Gynecology, School of
Medicine, J.W. Goethe University, Frankfurt, Germany (K.S.);
the Singapore Oncogenome Laboratory, Centre of Molecular
Medicine, Institute of Molecular and Cell Biology, Proteos,
Singapore (A.U.); and the Department of Molecular Biology, Max
Planck Institute of Biochemistry, Martinsried, Germany (A.U.).
Kerkelä R, Grazette L, Yacobi R, et al. Cardiotoxicity of the
cancer therapeutic agent imatinib mesylate. Nat Med 2006;12:
Urano F, Wa ng X, Bertolot t i A, et a l. Coupl i ng of st ress i n t he
ER to activation of JNK protein kinases by transmembrane pro-
tein kinase IRE1. Science 2000;287:664-6.
Godl K, Wissing J, Kurtenbach A, et al. An efficient proteo-
mics method to identify the cellular targets of protein kinase
inhibitors. Proc Natl Acad Sci U S A 2003;100:15434-9.
Noren NK, Foos G, Hauser CA, Pasquale EB. The EphB4 re-
ceptor suppresses breast cancer cell tumorigenicity through an
Abl-Crk pathway. Nat Cell Biol 2006;8:815-25.
Copyright © 2006 Massachusetts Medical Society.
Imatinib mesylate
Ultrastructural changes, collapse
of membrane potential
Cell membrane
Membrane of
Activation of
JNK pathway
Cell death
Stress in endoplasmic reticulum
Figure 1. Imatinib Mesylate and Signaling.
A recent study by Kerkelä et al.
indicates an association between imatinib
mesylate and congestive heart failure and provides insight into the mechanisms
underlying this association. Stress on the cell, such as energy depletion,
leads to the accumulation of unfolded proteins in the endoplasmic reticu-
lum that, in turn, activates stress-response mechanisms and apoptosis.
Kerkelä et al. have shown that imatinib may trigger the death of cardiomyo-
cytes by repressing the activity of c-ABL. When unfettered, c-ABL mutes
stress in the endoplasmic reticulum; thus, imatinib would seem to aug-
ment this stress (and, ultimately, apoptosis and necrosis) by removing the
“braking” effect of c-ABL. They also have shown that imatinib may act at a
second point, downstream of c-ABL. When unfolded proteins accumulate in
the lumen of the endoplasmic reticulum, IRE1 dimerizes, leading to Jun
N-terminal kinase (JNK) activation and hence the translocation of BAX (a pro-
apoptotic protein) to the mitochondria. The mitochondrial membrane subse-
quently collapses, and cytochrome c is released, causing the cell to undergo
apoptosis. Kerkelä et al. have shown that imatinib may mimic stress by acti-
vating JNK signaling.
Clinic al Implications of Basic Rese a rch
The New England Journal of Medicine
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Copyright © 2006 Massachusetts Medical Society. All rights reserved.
    • "Small molecule TK inhibitor-induced LV dysfunction is increasingly recognized, with the rapidly expanding panel of drugs that have received approval for use as therapy for a large variety of tumours. Treatment with imatinib mesylate has been reported to result in cardiac mitochondrial injuries and, in a few case reports, in LV dysfunction [25,26]. Whether imatinib mesylate induces heart failure in a significant subset of treated patients remains, however, under debate [27,28] . "
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    • "Conversely, inhibition of c-ABL after exposure to imatinib activates stress response pathways and apoptosis [105]. Although LV dysfunction induced by imatinib mesylate has been reversible in most instances after discontinuation of therapy, late persistent and irreversible heart failure has also been reported105106107. Imatinib mesylate-induced cardiac toxicity is also facilitated by several relevant co-morbidities such as previous cardiovascular disease or renal failure [107]. "
    [Show abstract] [Hide abstract] ABSTRACT: The spectrum of cardiac side-effects of cancer chemotherapy has expanded with the development of combination, adjuvant and targeted chemotherapies. Their administration in multiple regimens has increased greatly, including in older patients and in patients with cardiovascular and/or coronary artery disease (CAD). Cardiac toxicity of anthracyclines involves oxidative stress and apoptosis. Early detection combines 2D-echocardiography and/or radionuclide angiography and recent methods such as tissue Doppler imaging, strain rate echocardiography and sampling of serial troponin and/or NT-proBNP levels. Dexrazoxane has proven effective in the prevention of dose-related toxicity in children and adults. High doses of the alkylating drugs cyclophosphamide and ifosfamide may result in a reversible heart failure and in life-threatening arrhythmias. Myocardial ischemia induced by the antimetabolites 5-fluorouracil and capecitabine impacts prognosis of patients with prior CAD. Severe arrhythmias may complicate administration of microtubule inhibitors. Targeted therapies with the antibody-based tyrosine kinases (TK) inhibitors trastuzumab and, to a lesser extent, alemtuzumab induce heart failure or asymptomatic LV dysfunction in 1-4% and 10%, respectively. Cetuximab and rituximab induce hypotension, whereas bevacizumab may promote severe hypertension and venous thromboembolism. Small molecule TK inhibitors may also elicit LV dysfunction, in only few patients treated with imatinib mesylate, but in a substantially higher proportion of those receiving the multitargeted TK inhibitor sunitinib or the recently approved drugs erlotinib, lapatinib and dasatinib. Management of patients at increased cardiovascular risk associated with advancing age, previous CAD or targeted therapies may be optimized by referral to a cardiologist in a cross-specialty teamwork.
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  • [Show abstract] [Hide abstract] ABSTRACT: This introductory article to the review series entitled "The Cancer Cell's Power Plants as Promising Therapeutic Targets" is written while more than 20 million people suffer from cancer. It summarizes strategies to destroy or prevent cancers by targeting their energy production factories, i.e., "power plants." All nucleated animal/human cells have two types of power plants, i.e., systems that make the "high energy" compound ATP from ADP and P( i ). One type is "glycolysis," the other the "mitochondria." In contrast to most normal cells where the mitochondria are the major ATP producers (>90%) in fueling growth, human cancers detected via Positron Emission Tomography (PET) rely on both types of power plants. In such cancers, glycolysis may contribute nearly half the ATP even in the presence of oxygen ("Warburg effect"). Based solely on cell energetics, this presents a challenge to identify curative agents that destroy only cancer cells as they must destroy both of their power plants causing "necrotic cell death" and leave normal cells alone. One such agent, 3-bromopyruvate (3-BrPA), a lactic acid analog, has been shown to inhibit both glycolytic and mitochondrial ATP production in rapidly growing cancers (Ko et al., Cancer Letts., 173, 83-91, 2001), leave normal cells alone, and eradicate advanced cancers (19 of 19) in a rodent model (Ko et al., Biochem. Biophys. Res. Commun., 324, 269-275, 2004). A second approach is to induce only cancer cells to undergo "apoptotic cell death." Here, mitochondria release cell death inducing factors (e.g., cytochrome c). In a third approach, cancer cells are induced to die by both apoptotic and necrotic events. In summary, much effort is being focused on identifying agents that induce "necrotic," "apoptotic" or apoptotic plus necrotic cell death only in cancer cells. Regardless how death is inflicted, every cancer cell must die, be it fast or slow.
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