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338 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 339

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lymphoma harboring the mutation. Interestingly, loss-of-function kinase is the target for imatinib in the treatment of gastrointestinal stro-
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mutations of EZH2 in myeloid malignancies confer a worse prognosis, mal tumors, while activating mutations of PDGFR are the target of
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suggesting that EZH2 may act either as an oncogene or as a tumor sup- inhibition in the treatment of hypereosinophilia syndrome, chronic
pressor depending on context and site of mutation. myelomonocytic leukemia, MDS with PDGFR rearrangement 237A
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EZH2 inhibitors have been identified through high-throughput and dermatofibrosarcoma protuberans. Dasatinib and ponatinib also
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biochemical assays using mutant EZH2 with the PRC2 complex and inhibit the Src family kinases, an important secondary target in CML.
histone substrates. Preclinical data demonstrate increased EZH2 inhibitor Dasatinib (inhibiting growth by concentration 50 percent [IC ] =
50
selectivity for cell lines carrying activating EZH2 mutations. In mouse <1 nM), nilotinib (IC = <20 nM), bosutinib (IC = <1 nM), and
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50
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models with subcutaneous xenografts of diffuse large B-cell lymphoma ponatinib (IC = <1 nM and 10 nM for T315I) are more potent inhib-
50
cell lines harboring EZH2 activating mutations, marked tumor regres- itors of BCR-ABL compared to imatinib (IC = 100 nM). Crystallo-
50
sion was observed. Based upon these results, EZH2 inhibitors are now graphic and mutagenesis studies indicate that imatinib and nilotinib
in early phase 1 and phase 2 clinical trials in patients with relapsed and bind to a segment of the BCR-ABL tyrosine kinase domain that fixes
refractory diffuse large B-cell lymphoma with EZH2 mutations. 224 the enzyme in a closed or inactive state, in which the protein is unable
to bind its substrate, ATP. 240–242 The contact points between imatinib
Bromodomain and Extraterminal Inhibitors and the enzyme become sites of mutations in drug-resistant leukemic
The class of bromodomain and extraterminal (BET) family of proteins cells, preventing tight binding of the drug and locking the enzyme in its
couple histone acetylation with transcriptional activation by recogniz- active configuration, in which it has access to substrate. Nilotinib has
ing acetylated lysine residues in histones and recruiting members of been modified to overcome a number of resistance mutations to ima-
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the pTEF-b complex to promoters. BET proteins also interact with tinib. 239,241,243–245 Dasatinib is unique in that it is able to bind BCR-ABL
nonhistone acetylated proteins including p53. BET inhibitors selectively in both the active and inactive configuration, which may be one of the
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bind to the high conserved bromodomains of the BET proteins thereby mechanisms that allows it to overcome resistance. Importantly, pona-
inhibiting their ability to bind acetylated lysine residues within histones. tinib is the only agent with significant activity against the most common
Preclinical data with BET inhibitors demonstrate activity in both resistance mutation T315I, a gatekeeper mutation that prevents other
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myeloma and AML, particularly in cell lines containing MLL fusion TKIs from binding to the ATP binding site of BCR-ABL. 246
proteins or mutant NPM1c+. BET inhibitors induce early cell-cycle
arrest and apoptosis via inhibition of c-MYC and other downstream Clinical Pharmacology
targets. Survival benefits have also been seen in MLL mouse mod- The BCR-ABL kinase inhibitors are all well absorbed by the oral route
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els. HDAC and BET inhibitors act synergistically by maintaining both and subject to clearance by hepatic CYP3A4 metabolism. The absorp-
histone lysine residues and p53 in an acetylated state thereby inducing tion of dasatinib and ponatinib is pH-dependent and may be affected
greater reliance on BET mediated transcription. 227,228 Based upon these by the use of H blockers and proton pump inhibitors. The absorption
2
results the first BET inhibitors have entered early phase clinical trials. 229 of bosutinib may be impaired by concomitant magnesium intake. The
bioavailability of nilotinib is increased if taken with meals and therefore
should be taken on an empty stomach. Clearance of imatinib is delayed
SMALL MOLECULES WITH SPECIAL in patients with renal dysfunction, apparently as a result of decreased
MOLECULAR TARGETS P450 activity in the presence of renal failure. Limited data indicate that
imatinib penetrates poorly into the cerebrospinal fluid, achieving con-
centrations of 1 percent of simultaneous drug levels in the systemic cir-
BCR-ABL TYROSINE KINASE INHIBITORS culation. There are no data about the penetration of other BCR-ABL
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The era of targeted cancer therapy was pioneered in the treatment of inhibitors in the cerebral spinal fluid.
CML with imatinib mesylate. This carefully designed compound is an All FDA-approved BCR-ABL inhibitors are more than 94 percent
inhibitor of ABL tyrosine kinase activity and particularly efficacious protein bound, largely by α -acid glycoprotein, a binding protein pres-
1
against the mutant ABL characteristic of the BCR-ABL fusion protein. ent in higher concentrations in humans than in mice. Thus, therapeu-
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This protein is a result of the translocation t(9;22)(q24,q11.2), also known tic studies in mice may overpredict drug activity. α -Acid glycoprotein
1
as Philadelphia chromosome, a transforming genetic event, which pro- concentrations vary over a fourfold range in human subjects, and total
duces growth factor independent proliferation and sensitizes affected drug concentrations in plasma appear to be a function of α -acid glyco-
1
leukemic cells to inhibition with imatinib and other tyrosine kinase protein levels. Drugs that compete for binding sites with α -acid glyco-
1
inhibitors (TKIs). Imatinib was selected for clinical study by scientists protein, such as clindamycin, displace imatinib mesylate from binding
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at Ciba-Geigy (later Novartis) based on a high-throughput screen for to α -acid glycoprotein and, in mice, increase the concentration of drug
1
kinase inhibition and was the first drug of this class approved in 2001 found in cells.
for the treatment of CML based on the large phase III International There is significant variability among different BCR-ABL inhibitors
Randomized Study of Interferon and STI571 (IRIS) trial, which showed with regard to their bioavailability. Imatinib has the highest bioavail-
induction of durable remissions in a large proportion of patients. 231,232 ability (98 percent), followed by bosutinib (23 to 64 percent), nilotinib
Since then the three additional second-generation agents dasatinib, (50 percent), and dasatinib (14 to 34 percent), while the bioavailability
nilotinib and bosutinib, as well as the third-generation TKI pona- is unknown for ponatinib.
tinib, have been approved for imatinib-refractory or intolerant patients Despite their unparalleled benefit in the treatment of patients with
(Table 22–5). Another non-TKI agent, omacetaxine is approved for CML and other malignancies, resistance to TKIs represent a major
patients with resistance or intolerance to two or more TKIs. 233 limitation. Although there are multiple mechanisms of resistance, one
can divide resistance to TKIs into two general categories: primary resis-
Mechanism of Action tance, which refers to a de novo lack of response to a drug, and second-
Imatinib, nilotinib, dasatinib, bosutinib, and ponatinib (Fig. 22–7) are ary (acquired) resistance, in which resistance to a drug emerges after
all inhibitors of the BCR-ABL kinase, as well as the c-KIT kinase and a period of drug response. The most important and most frequently
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the platelet-derived growth factor receptor (PDGFR) kinase. The c-KIT found resistance mechanisms to TKIs are point mutations in three

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