US Pharm. 2008;33(10)(Oncology
suppl):3-14,23.
ABSTRACT:
Tyrosine kinases are a family of proteins that contribute to the development
of cancer. Anticancer drug development has recently taken aim at these
receptors. The tyrosine kinase inhibitors (TKIs) are a class of
small-molecule, orally administered agents with a unique mechanism of action.
Since these drugs are administered orally, they can be dispensed in any
practice setting. The purpose of this article is to provide an overview of
TKIs and review important considerations for dispensing these agents.
Traditionally,
the pharmacologic management of cancer utilized primarily IV medications and
was therefore dismissed as having little relevance to the community
pharmacist. However, recent developments in the field of targeted therapy are
starting to erode this paradigm. Since the start of the new millennium,
small-molecule, orally administered drugs that target specific tumorigenic
proteins have been available to treat cancers. These tumorigenic proteins,
known as tyrosine kinases, can be subdivided into two broad classes
based upon their structure, function, and localization. Both receptor tyrosine
kinases (RTKs) and nonreceptor tyrosine kinases (NRTKs) have been implicated
in the development of multiple types of cancer including, but not limited to,
leukemia, lung cancer, breast cancer, pancreatic cancer, and gastrointestinal
stromal tumors (GISTs). Agents that target these proteins have a number of
distinct advantages over conventional chemotherapy including a reduction in
systemic toxicity and the ability to be administered orally.
As additional oral,
small-molecule targeted therapies become available, the community pharmacist
will become more involved in the care of cancer patients. These patients will
expect their pharmacists to provide counseling regarding these new drugs.
Therefore, pharmacists should, at minimum, understand the pathobiology,
pharmacology, indications, side effects, and drug interactions of these agents.
Pathobiology
Receptor
Tyrosine Kinases:
RTKs are a superfamily of cell membrane proteins that possess common
structural features to include an extracellular ligand-binding domain, a
transmembrane region, and a cytoplasmic region containing adenosine
triphosphate (ATP)–binding and enzymatic kinase domains (FIGURE 1).
There are approximately 60 known and characterized RTKs that are divided into
at least 20 subfamilies based on similar receptor characteristics and/or
common ligands.1 These proteins are critical in capturing and
transducing extracellular signals carried by peptide-based ligands, referred
to as growth factors. Their signals help regulate normal cellular
processes associated with cell life span, cellular proliferation, and
differentiation.
In their inactive state, RTKs
exist as monomeric transmembrane proteins (FIGURE 1A). Once activated,
these proteins dimerize and form oligomeric pairs. The formation of receptor
oligomers is coupled to the activation of the receptors' enzymatic domains and
autophosphorylation of tyrosine residues contained within the intracellular
domain of the receptor (FIGURE 1B). Phosphorylation of tyrosine
residues on the receptor and effector proteins occurs when ATP binds to a
specific region of the receptor. Once bound, the receptor removes a phosphate
group from ATP and transfers it to a tyrosine residue on either the receptor
or effector protein. Phosphorylated tyrosines on the receptor are thought to
serve as docking sites for a variety of effector proteins that participate in
multiple signal transduction cascades coupled to these receptors. Once docked,
these effector proteins can be activated by the receptor through additional
phosphorylation reactions (FIGURE 1C).2,3
It is evident that ATP binding
is a critical component of RTK activity. If the ability of these receptors to
bind and utilize ATP is impaired, their activity will be greatly diminished.
This serves as a key component of targeted therapy activity.2,3
While RTKs play an important
role in the normal regulation of many cellular processes, when abnormalities
occur in their expression (i.e., autoregulatory mechanisms, intracellular
signaling, or responsiveness to extracellular ligands), they can cause cells
to divide uncontrollably, thus participating in the pathobiology of cancer. It
is now apparent that the activity of a specific subclass of RTKs (subclass 1
or ERBB) is abnormal in many types of epithelial cancers. There are four
members of the ERBB subclass: ERBB1, ERBB2, ERBB3, and ERBB4. The nomenclature
for these receptors can be confusing, as there are multiple designations for
each receptor subtype, and all are used interchangeably in the literature. For
example, the ERBB1 receptor is also commonly referred to as the epidermal
growth factor receptor (EGFR) or the human epidermal growth factor receptor
(HER1). The ERBB2, ERBB3, and ERBB4 receptors also have multiple designations,
commonly referred to in the literature as EGFR2, HER2/neu, HER3, and HER4,
respectively.
Other RTKs that appear to be
important in tumor development include vascular endothelial growth factor
receptors (VEGFR, VEGFR2) and platelet-derived growth factor receptors
(PDGFRs). These receptors have been identified as important mediators of blood
vessel growth into tumors (angiogenesis), as well as promoters of tumor
metastases. VEGFRs and PDGFRs have a number of basic similarities to ERBB
receptors with respect to activation, oligomerization, and autophosphorylation.4
Overexpression of these receptors and/or their associated ligands has been
linked with increased vascularization of solid tumors, an increase in the
recurrence of cancers, and a decrease in patient survival.5
In addition, the FMS-related
tyrosine kinase-3 receptor (FLT3) is expressed by early hematopoietic
progenitor cells and plays an important role in the development of these
cells. Mutations in FLT3 can cause constitutive activity, contributing to
disregulated division of hematopoietic progenitor cells and leading to the
development of acute myelogenous leukemia.6
With the overwhelming evidence
that this family of receptors is so important in the pathobiology of cancer,
it is not surprising that developing compounds to inhibit these receptors has
become a major focus in cancer therapy research.
Nonreceptor Tyrosine
Kinases: NRTKs are a
diverse group of cytosolic proteins found in various regions of the cell,
including the inner surface of the plasma membrane and nucleus. Like their
membrane counterparts, these proteins play an important role in regulating
cell proliferation, differentiation, metabolism, migration, and survival by
participating in cellular signaling cascades that are activated by a variety
of signals to include hormones, neurotransmitters, growth factors, and
cytokines. Currently, there are nine families of NRTKs, with multiple members
in each family. They are the ABL (Abelson), Src, Tec, CSK, FAK, SYK, JaK, TnK,
and FeS families.7 Functionally, each class of NRTKs works by
catalytically transferring a phosphate group from ATP to a tyrosine residue on
an effector polypeptide/protein. As with the RTKs, the transfer of a phosphate
group from ATP to an effector protein is an important component for regulating
the activity of signaling cascades that help govern cellular processes such as
proliferation and differentiation.
Given the role of NRTKs in
cellular function, it is not surprising that their activity is kept under
tight control by the cell. Like their receptor counterparts, when these
proteins cease to function normally due to genetic mutation, leading to
abnormal signaling, loss of autoregulatory processes, or overexpression, they
can participate in the pathology of many types of cancer.8
Therefore, it is not surprising that this group of proteins has also become an
important therapeutic target for the treatment of neoplastic disease.9
One NRTK in particular, c-ABL,
has been studied extensively and been shown to play an important role in the
development of chronic myelogenous leukemia (CML). Normally, c-ABL
participates in a number of cellular processes, including regulation of the
cell cycle.10 However, in CML patients, a chromosomal abnormality
is present that alters the structure and activity of this NRTK. Known as the
Philadelphia chromosome (Ph), this defect occurs when pieces from two
chromosomes, 9 and 22, which contain the genes for c-ABL and breakpoint
cluster region (BCR), respectively, become translocated and fused together.
The resulting hybrid, the BCR-ABL oncogene, produces an NRTK that has
the propensity to oligomerize, becoming hyperactive and unregulatable.11
This genetic abnormality is seen in 95% of patients with CML and between 15%
and 30% of patients who have acute lymphoblastic leukemia.12,13
Pharmacology
Small-molecule
tyrosine kinase inhibitors (TKIs) are a group of orally available compounds
that selectively target and inhibit RTKs and NRTKs. These therapies have
significant advantages over traditional chemotherapy in that they target
specific proteins that are known to have important roles in tumor growth and
progression. Because of their pharmacologic specificity, these agents tend to
preferentially impact tumor cell function, thus sparing normal cells and
reducing much of the systemic cytotoxicity associated with more traditional
agents.14 Furthermore, because of their unique toxicity profiles,
these agents can be used in conjunction with radiation therapy and more
traditional cytotoxic agents to improve the anticancer activity of a given
therapeutic regimen. The primary mechanism of the small-molecule TKIs is to
inhibit abnormal signals generated by RTKs and NRTKs that lead to the
formation of neoplastic cells. Because of their unique chemical structures,
these compounds are able to bind to and block the ATP-binding sites on
tyrosine kinases. With an impaired ability to bind ATP, the kinase activity of
these proteins is reduced, and they are unable to phosphorylate tyrosine
residues located on their cytoplasmic domains and effector proteins. Once
inhibited, the neoplastic cells may stop replicating abnormally and/or undergo
apoptosis (programmed cell death).
Growth factor signaling
through RTKs can activate multiple signaling pathways that are interconnected
through common effector proteins and/or the activation of one effector protein
by another in a separate signaling cascade. This "crosstalk" between receptors
and signaling pathways can make inhibition of a single receptor or effector
protein therapeutically irrelevant if an accessory pathway can continue to
generate and carry the cellular signals that are responsible for abnormal
cellular proliferation. Additionally, some tumors are dependent on multiple
defects in receptor and enzyme signaling. Drugs that can inhibit the proteins
responsible for these defects may work better in some cancers than in those
that are more selective. Therefore, depending on the pathology of the cancer
in question, the selectivity and specificity of a TKI may be an important
determinant of its therapeutic usefulness. For example, in cancers like CML,
neoplastic cell development is highly dependent on one major genetic defect,
the BCR-ABL oncogene. In this case, a compound like imatinib, which is highly
selective for the BCR-ABL tyrosine kinase, is very effective. This is a
practical example of the biological phenomenon known as oncogene addiction.15
In contrast, many types of
solid tumors are only partially responsive to tyrosine kinase inhibition. The
pathology of these types of cancers may be multifactorial and caused by
intracellular signaling abnormalities in more than one receptor and
transduction pathway and, as such, may not respond to therapies that
antagonize the activity of only one cellular protein.16 Some
compounds (e.g., lapatinib, erlotinib) are very specific and selective for
only one kind of RTK, while some of the newer agents on the market (e.g.,
dasatinib, nilotinib, sunitinib) are relatively nonspecific and can inhibit
multiple RTKs.
Resistance to small-molecule
therapy is a phenomenon that has been well documented and shares many
similarities with mechanisms of resistance to traditional chemotherapy. These
include mutations to target proteins that impair drug binding, increased
ability to extrude drug from the cytoplasm, an increased reliance on a
secondary signaling pathway that continues to support abnormal growth or
proliferation, and permanent activation of downstream signaling molecules that
are unaffected by inhibiting proteins higher up in the signal transduction
cascade.
An excellent practical example
of tumor cell resistance to small-molecule TK inhibition is the development of
imatinib resistance in CML. In CML, imatinib is first-line therapy, and
resistance to therapy can develop. This drug inhibits the BCR-ABL tyrosine
kinase, leading to an inhibition of cellular proliferation and an induction of
apoptosis. Resistance to therapy can develop in patients who have been
receiving imatinib therapy for several years or where relapse occurs; the
leukemia cells often express a mutated form of the BCR-ABL that is resistant
to imatinib inhibition. The specific mutation lies in the ATP-binding pocket
near the catalytic domain, and because of its strict binding requirements,
this affects the ability of imatinib to inhibit the activity of BCR-ABL.
Fortunately, another small-molecule inhibitor, dasatinib, because of its less
stringent binding requirements, is still able to bind to the ATP-binding
pocket of the mutated form of BCR-ABL and inhibit it. Another way in which
resistance develops is that tumor cells often have the ability to switch from
one receptor signal transduction pathway that is being inhibited to another,
which will continue to support abnormal proliferation and survival.17
Indications
Currently, the TKIs
are FDA approved to treat breast, lung, pancreatic, and kidney cancer, as well
as GIST (TABLE 1).18-24 Lapatinib is an inhibitor of HER2
(ERBB2) and is used for the treatment of breast cancer in combination with
capecitabine.18 Erlotinib and gefitinib inhibit EGFR-1 (ERBB1) and
are FDA approved for the treatment of non-small cell lung cancer (NSCLC) after
failing chemotherapy.19,20 Erlotinib also has an indication for the
treatment of pancreatic cancer in combination with gemcitabine.19
Based on revised labeling, gefitinib's use is limited to patients who have
previously taken the drug and are benefiting or have benefited from it.20
The BCR-ABL inhibitors imatinib, dasatinib, and nilotinib are used to treat
CML.21-23 Interestingly, these drugs also inhibit the cytokine
receptor c-KIT and display activity against GIST. Sunitinib is indicated for
the treatment of advanced renal cell carcinoma and GIST.24 Most of
these agents are also undergoing investigations for other cancers, such as
colon and head/neck.25
The TKIs currently available
commercially are somewhat selective in their activity, in that they mostly
inhibit one or two TK receptors. However, the TKIs in the current development
pipeline tend to inhibit many different types of tyrosine kinases. These
"multikinase" inhibitors represent the second generation of TKIs that would
theoretically have a broader spectrum of activity and would hopefully be used
to treat various types of cancer.
Clinical Data and
Applications
As a class, the
TKIs have relatively limited data compared to most other cytotoxic
chemotherapy used for the same cancer. Therefore, most of the clinical data
currently available demonstrate their use primarily in the metastatic stage of
cancer. For example, erlotinib currently only has data demonstrating response
in metastatic lung and pancreatic cancer, while lapatinib's results are for
metastatic breast cancer. Generally, the results in clinical trials have not
been particularly impressive (i.e., erlotinib improves overall survival by 2
months and lapatinib delays progression by 4 months).26,27
Nonetheless, these numbers can be clinically significant to a cancer patient
or family members. Moreover, these oral agents can be attempted as first-line
therapy for patients who cannot tolerate chemotherapy because their poor
performance status would leave them susceptible to chemotherapy morbidity and
mortality. As we develop more experience with this class of drugs, their use
may expand into the adjuvant setting, perhaps even as part of a chemotherapy
regimen.
One exception to this
last-line rule is imatinib's role in treating CML. Because imatinib
demonstrates excellent long-term response rates along with minimal toxicity
compared to the alternative (i.e., interferon, chemotherapy), it is the
recommended first-line agent to treat chronic phase CML.28,29 There
are some patients who have disease resistant to imatinib. In these situations,
dasatinib and/or nilotinib are used to overcome imatinib-resistant disease.
Adverse Effects
It is important to
note that TKIs are not cytotoxic chemotherapy and, therefore, do not exhibit
the worrisome adverse effects of myelosuppression, hair loss, kidney damage,
or peripheral neuropathy. Instead, these drugs are touted as being "well
tolerated" by many practitioners. This term should not be misconstrued as
meaning "the absence of side effects." Rather, it is a statement of comparison
to the aforementioned effects of chemotherapy.
Rash:
An erythematous, maculopustular rash (also referred to as an acneiform
rash) is an important adverse effect associated with the EGFR1 inhibitors
erlotinib and gefitinib. This rash commonly presents on the face, neck, and
trunk area. Although not life threatening, it is uncomfortable and can be
disfiguring. On a positive note, the rash is correlated with response to
therapy in clinical trials. Therefore, it can be a reassuring sign to patients
that their therapy is working. Mild skin eruptions may be treated with OTC
topical antiacne medications, while more severe cases may require treatment
with oral antibiotics (e.g., minocycline or tetracycline). If the rash is
extremely severe and disfiguring, the offending drug may need to be
discontinued or held.30
Diarrhea:
In clinical trials, diarrhea was a common adverse effect with all of the TKIs,
with an incidence of up to 50% of patients.19 The diarrhea is
unlikely to resolve on its own. Loperamide may be used to control these
symptoms. Alternatively, a reduction in the TKI dose may be considered.
Interstitial Lung
Disease: Perhaps the
most dangerous adverse effect with the EGFR TKIs erlotinib and gefitinib is
the risk for interstitial lung disease (ILD). The incidence of ILD is low,
with less than 1% occurring in U.S. clinical trials but upward of 4% in the
Japanese population.31 The mechanism for this adverse effect is not
clearly understood, but it is thought that EGFR plays an important role in
repairing lung damage. Inhibiting this pathway would allow patients to be more
susceptible to acute lung injuries. Patients should be told that this is a
life-threatening event, and any acute sign of shortness of breath and cough
with fever should require immediate medical attention. Therapy with the TKI
should be held until ILD can be ruled out.31
Neutropenia:
Neutropenia is a concern only with imatinib, dasatinib, and nilotinib, the
TKIs that target the BCR-ABL fusion protein found in leukemia. This is most
likely due to the nature of the disease, rather than to the drug's direct
cytotoxic effect on neutrophil progenitor cells. For example, clinical trials
observed a higher frequency of neutropenia in patients with more advanced
leukemia. Additionally, Phase I studies with imatinib observed a dose-related
relationship with neutropenia.21 Therefore, patients should be told
that their physician will be monitoring their white blood cell count and will
adjust their dose if necessary.
Hepatic Toxicity:
Hepatotoxicity is also a concern specific to the BCR-ABL inhibitors. Clinical
trials with imatinib, dasatinib, and nilotinib reported elevations in
bilirubin and other liver function tests associated with the drugs.21-23
Therefore, it is important to monitor the patient's liver function at routine
intervals (e.g., monthly) while these medications are being taken.
Furthermore, the concomitant use of acetaminophen is generally not recommended
because of the increased potential for liver toxicity. In fact, there was one
case of acute liver failure in the setting of concomitant acetaminophen and
imatinib use that resulted in the patient's death.21
Drug Interactions
All currently
available TKIs are substrates of CYP3A4. Additionally, imatinib inhibits
CYP2D6 and nilotinib inhibits 2C8, 2C9, and 2D6. Dose adjustments to the TKIs
are necessary when coadministering with potent CYP inhibitors or inhibitors,
such as azole antifungals or rifampin. Specific dose adjustments for each drug
can be found in the prescribing information.18-24
Counseling Points
When counseling
individuals regarding these medications, it is important that patients have
realistic expectations of therapy. Most TKIs do not cure the disease. Rather,
they prolong disease progression and improve survival. Conversely, imatinib
has displayed high long-term remission rates in CML, effectively "curing" most
patients as long as they remain on the drug. Data are too preliminary to make
the same conclusions with dasatinib and nilotinib.29 Pharmacists
must proceed with caution when discussing expectations of therapy, since it is
unknown what was already discussed with the oncologist.
Since a major adverse effect
with the EGFR inhibitors is an acnelike rash, patients should be told to
expect this reaction and contact their physician if it occurs. Recommending an
OTC acne medication without a physician's evaluation is not appropriate.
However, the presence of the rash can be reassuring, since clinical studies
have demonstrated a correlation between this rash and response to therapy.30
A very common question from
patients to pharmacist about any medication is how to take the drug with
regard to meals. With TKIs, there is no consistency in this area. Therefore,
each TKI will have its own recommendation about taking the drug with or
without food. Even more confusing is the rationale for such recommendations;
sometimes they are counterintuitive. For example, lapatinib's recommendation
is to take on an empty stomach (1 hour before or after a meal), but the
pharmacokinetic profile shows increased absorption with a fatty meal (area
under the curve [AUC] about four times higher with food than without).18
One would think the patient should take the drug with food to maximize
exposure and hopefully boost efficacy. However, it should be noted that the
clinical trials specified taking the drug on an empty stomach. As such, we are
unsure about what additional toxicities patients may experience because of the
increased systemic exposure from taking the drug with food. Therefore, it is
best to recommend taking each drug exactly as the prescribing information
indicates (TABLE 2).18-24
Summary
Small-molecule TKIs represent one of the newest additions to the already vast array of therapeutic agents available to treat cancer. While tyrosine kinase inhibition is clearly a viable pharmacologic strategy for the treatment of many types of cancer, it is not a widespread cure for the disease. There appears to be a role for protein tyrosine kinases in the development of many, but not all, types of cancers. The effectiveness of these therapies depends largely on the specific pathology of the cancer in question. Their oral availability, selective nature, and relative lack of systemic toxicities make these drugs an exciting new treatment paradigm. It is apparent that the community pharmacist, who in the past had little or no role in the treatment of cancer, can and will play a more important role by dispensing and counseling patients about these agents.
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