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Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 863

ABL in its inactive form as imatinib. Differences in the chemical AKT signals to multiple downstream targets, in particular
structure allow ponatinib to maintain interaction with ABL even in mTORC1, to promote cell survival and growth. Additional targets
the presence of isoleucine in position 315, in cases with a T315I of AKT include molecules involved in cell survival and proliferation
mutation. Initial cell- and murine-based studies showed that pona- (e.g., Bad, Bim, procaspase 9, CREB, forkhead transcription factors
tinib inhibits cells expressing mutant or native BCR-ABL. Subsequent [FHKR], IB), cell cycle regulators (p21 CIP1 , p27 KIP1 , cyclin D 1 ), gly-
S6K
human studies demonstrated that ponatinib had activity in CML, cogen synthesis (GSK3), and protein synthesis (FRAP1, p70 ).
including those with T315I mutation. Toxicities observed in early The mechanistic target of rapamycin (also known as mTOR)
clinical trials included pancreatitis and elevation in pancreatic operates through two complexes: mTORC1 (mTOR-Raptor) and
enzymes, fatigue, rash, and elevated aminotransferase levels. Ponatinib mTORC2 (mTOR-Rictor). mTORC1 is activated by AKT and
received FDA-accelerated approval in 2012 for the treatment of mediates its downstream proliferation, growth, and survival signaling,
resistant or intolerant CML and Ph+ ALL. However, subsequent specifically through phosphorylation and inactivation of the repressor
trials showed increased arterial thrombosis events in patients random- of mRNA translation initiation factor 4E-binding protein 1 (4E-BP)
ized to ponatinib arms, leading to limitations in the indications for and ribosomal protein S6 kinase 1 (S6K1; see Fig. 57.6), resulting in
ponatinib and the requirement for thrombosis prevention strategies enhanced translation of transcripts relevant to lymphoma pathogen-
in subjects treated with this drug. esis, including CCND1, MYC and MCL1. The mTORC1 complex
is activated by AKT whereas mTORC2 is capable of activating AKT.
The majority of the downstream canonical functions are conduced
Bruton Tyrosine Kinase Inhibitors by mTORC1.
Because of the frequency of PTEN losses or mutations (less
Btk is a cytoplasmic TK with a well-defined role in B-cell receptor common in hematologic malignancies) in transformed cells and the
signaling that is fundamental in B-lymphocyte development, differ- dependence of numerous cancers on an intact PI3K/AKT/mTOR
entiation, and signaling. Btk is a member of the Tec family of kinases pathway for survival, this cascade has become an attractive therapeutic
(see Chapter 77). Activation of Btk triggers a cascade of signaling target.
events that culminates in the generation of calcium mobilization and
fluxes, cytoskeletal rearrangements, and transcriptional regulation of
5
NFκB and nuclear factor of activated T cells. Ibrutinib (PCI-32765)
is a first-in-class, selective, irreversible, small-molecule inhibitor of
Btk. Ibrutinib binds covalently to a cysteine (Cys 481) in the Btk
active site, with potent and irreversible enzymatic activity. Clinical
trials demonstrated a favorable toxicity profile with remarkable clini- PI3K PTEN
cal activity in patients with relapsed CLL, mantle cell lymphoma
(MCL), and Waldenström macroglobulinemia, with additional activ-
ity observed in activated B-cell–like diffuse large B-cell lymphoma P
and other lymphoid malignancies. AKT P TSC1-TSC2
An early transient phase of lymphocytosis has been associated
with response in CLL and MCL patients. Bruising can be observed
in up to half of patients treated with ibrutinib. Serious adverse Rapamycin P
events associated with ibrutinib occurred in approximately 10% CC1-779 mTOR RHEB
of patients, including rash, febrile neutropenia, diarrhea, and life RAD-001
threatening bleeding. The diarrhea follows two patterns: an early Raptor
diarrhea that usually presents in the first weeks of treatment, which
can usually be managed with antidiarrheal agents, and a late diar- P
rhea that has an inflammatory bowel component and that may P P P
require more aggressive therapies, including corticosteroids and S6K1 4EBP1
other antiinflammatory therapies. Atrial fibrillation or flutter has
been observed in 6%–9% of patients. The mechanism for increased
bleeding risk appears to be related to a platelet function defect
secondary to interference of collagen receptor glycoprotein VI P P P
signaling. S6 eIF4B eIF4E
Dosing for CLL and Waldenström’s macroglobulinemia patients
is 420 mg PO once daily; MCL patients is 560 mg once daily.

PI3K/AKT/mTOR Inhibitors Translation-initiation of mRNA with highly structured 5'UTR
(C-MYC, CYCLIN D1, etc.)
The PI3K/AKT/mTOR pathway is involved in the regulation of Fig. 57.6 RAPAMYCIN OR ITS ANALOGS INHIBIT MAMMALIAN
diverse cellular functions, including cell growth, protein synthesis, TARGET OF RAPAMYCIN AND THE DOWNSTREAM PHOSPHORY-
cell cycle regulation, glucose metabolism, and motility. PI3K repre- LATION OF S6K1 AND 4EBP1, THEREBY ATTENUATING THE
sents a family of enzymes with multiple subunits. These subunits TRANSLATION INITIATION OF mRNAS WITH HIGHLY STRUC-
cooperate to transduce upstream signals (from RTKs, G-protein– TURED 5′-UTR. Activation of the receptor (FLT-3) or cytosolic tyrosine
coupled receptors, and other intracellular stimuli) into the enzymatic kinase (e.g., BCR-ABL) can lead to increased activity of PI3K/AKT. Although
conversion of phosphatidylinositol diphosphate (PIP 2), to phospha- it can directly phosphorylate mTOR, AKT activity inhibits the TSC1–TSC2
tidylinositol triphosphate (PIP 3). The dual-specific phosphatase and complex, thereby derepressing RHEB and activating mTOR. The phosphory-
tensin homolog (PTEN) opposes the actions of PI3K. PTEN is one lation and activation of S6K1, and phosphorylation and inactivation of
of the most frequently mutated tumor suppressor genes in human 4E-BP through Raptor, results in the phosphorylation of S6, eIF4B, and
malignancies, with inactivating mutations, genetic losses, and epigen- eIF4E, which are involved in the cap-dependent translation of mRNAs with
etic silencing leading to PTEN loss. Phosphatidylinositol triphos- highly structured 5′-UTR. eIF, Eukaryotic translation initiation factor;
phate, through phosphoinositoside-dependent kinase-1 (PDK1), mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinas;
leads to the phosphorylation and activation of the serine/threonine PTEN, phosphate and tensin homolog; RHEB, Ras homolog enriched in
kinase AKT. brain; TSC, tuberous sclerosis; UTR, untranslated region.