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Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 865

The most common side effect of rapalogs is myelosuppression; The major activator of MEK1/2 is the serine-threonine kinase
other common side effects include fatigue, oral ulcers, and dermato- RAF, of which three forms exist: RAF1, B-RAF, and A-RAF. RAF can
logic abnormalities. Metabolic abnormalities are common, including be activated by Ras (discussed earlier), as well as through various
hyperglycemia, hypercholesterolemia, and hypertriglyceridemia. An RAS-independent pathways, including PKC, KSR, as well as the SRC
uncommon pulmonary toxicity manifested as interstitial lung disease and JAK family of kinases, among others. The activation of RAF
has also been observed with rapalogs. involves several processes, including recruitment to the plasma
membrane, phosphorylation on serine and threonine residues, and
dimerization. Interference with any of these processes can lead to
Anaplastic Lymphoma Kinase Inhibitors inhibition of Raf activation as well as downstream targets.
Dysregulation of the RAF/MEK/ERK pathway has been observed
Anaplastic lymphoma kinase (ALK) encodes for a 210-kDa RTK, a in most hematopoietic malignancies, including acute leukemia, CLL,
member of the insulin receptor superfamily closely related to leuko- MM, and lymphomas. Consequently, there has been considerable
cyte TK. While ALK has a normal role in nervous system develop- interest in the development of pharmacologic inhibitors of the RAF/
ment, translocations involving ALK have been described in a variety MEK/ERK pathway in these disorders. In addition to their potential
of malignancies, including anaplastic large-cell lymphoma (NPM- intrinsic activity against malignant hematopoietic cells, evidence
ALK, TFG-ALK, ATIC-ALK, and CLTC-ALK translocations), indicates that such agents might also enhance the activity of conven-
DLBCL (NPM-ALK, CLTC-ALK, SQSTM1-ALK, and SEC31A- tional cytotoxic drugs.
ALK translocations), as well as non-small-cell lung cancer (NSCLC;
EML4-ALK translocation and others). These translocations result in Sorafenib
ALK chimeras, with fusion of the intracytoplasmic domain of ALK Initial approaches to RAF inhibition focused on efforts to destabilize
with partner proteins that provide a dimerization domain that results the protein. For example, geldanamycin and the related compound
in ALK-mediated autophosphorylation and constitutive activation. 17-AAG act as inhibitors of HSPCA, a chaperone protein necessary
Subsequent signaling promotes cellular proliferation, survival and for Raf processing and stabilization. Interference with HSPCA results
growth via phospholipase Cγ, RAS/mitogen-activated protein kinase in destabilization and proteasomal degradation of RAF as well as
(MAPK), PI3K and c-Src. numerous other proteins, including AKT. More recently, however, a
Raf kinase inhibitor, sorafenib, which is approved for use in kidney
Crizotinib cancer, has been developed and has entered phase I and II clinical
Crizotinib is a dual ALK/c-MET inhibitor with additional inhibitory trials in humans with leukemia. In preclinical studies, induction of
activity against the kinase ROS1 (c-ros). It inhibits kinase activation leukemic cell death by sorafenib has been shown to stem from inhibi-
through binding to the kinase domain and displacing the kinase tion of translation and downregulation of the short-lived antiapoptotic
activation loop, interfering with ATP and substrate binding. Crizo- protein Mcl-1 and induction of endoplasmic reticulum (ER) stress
tinib was shown to be 20-fold more selective for ALK and MET than with bim-mediated apoptosis. In the clinical setting, modest response
other kinases, and inhibited cell proliferation and induced apoptosis rates of 10% were observed in two studies, suggesting the need to
in NPL-ALK–dependent cell lines. The initial clinical studies done consider combination therapy.
in patients with NSCLC showed the maximum tolerated dose was
250 mg PO twice daily. Although initially tested as a c-MET inhibi-
tor in these patients, ALK translocations were reported to be associ- Janus Kinase 2 Inhibitors
ated with marked responses in patients treated with crizotinib.
Subsequent studies in ALK-rearranged NSCLC confirmed the activ- JAK2 is a non-RTK that plays a central role in the transduction of
ity of crizotinib in NSCLC with ALK translocations. In 2011, the differentiation and proliferation signals in hematopoietic progenitor
FDA granted approval for crizotinib in this patient population. cells. Ligand binding to surface receptors for hematopoietic growth
Subsequent studies conducted in relapsed and refractory ALK-positive factors leads to phosphorylation of JAK2 with subsequent activation
anaplastic large-cell lymphoma showed a high rate of response to of transcription factors in the JAK/signal transducer and activator of
single-agent crizotinib. Additional trials testing crizotinib for ALK- transcription (STAT) pathway, including STAT3 and STAT5 (see
positive lymphomas are ongoing. Chapters 68–70). Identification of the JAKV617F mutation in
The most common adverse events include gastrointestinal symp- patients with myeloproliferative neoplasms, including polycythemia
toms (nausea, vomiting, diarrhea), visual impairment, asthenia, vera, essential thrombocythemia, and primary myelofibrosis, repre-
cough, and myelosuppression (neutropenia, lymphopenia), as well as sented a fundamental step in understanding the pathophysiology of
elevations of hepatic function tests. these disorders. The genetic abnormality corresponds to a point
mutation in nucleotide 1849 of the molecule, where guanine replaces
thiamine, resulting in substitution of a valine for phenylalanine in
Inhibitors of the RAF1/Mek/ERK Pathway the JH2 pseudokinase autoinhibitory domain of the molecule. The
result is either hypersensitivity to cytokine signals or constitutive
The MAPK pathways consist of three parallel serine-threonine kinase activation of the kinase. Development of JAK2 inhibitors followed
modules that are intimately involved in the control of cell survival, as a rational, targeted therapeutic strategy for these neoplasms (see
proliferation, and differentiation. Two of these, c-Jun N-terminal Chapters 68–70).
kinase (JNK) and p38 MAPK, are activated in response to envi-
ronmental stresses, including DNA damage and osmotic stress, Ruxolitinib
but p42/44 MAPK (also known as extracellular signal-regulating Ruxolitinib (INCB018424, Jakafi) is a small-molecule inhibitor of
kinase [ERK]) is primarily induced by growth factors and other JAK1 and JAK2, and the first-in-class JAK inhibitor to receive FDA
mitogenic stimuli. Although exceptions exist, JNK and p38 MAPK approval for treatment of intermediate- and high-risk myelofibro-
primarily exert proapoptotic functions, but ERK activation is gener- sis 10,11 (see Chapter 70). It exerts its inhibitory activity through
ally associated with cell survival. The only well-defined activator competitive inhibition of the kinase’s ATP-binding catalytic site. In
of ERK is the serine-threonine kinase mitogen-activated protein preclinical studies, JAK1/2 inhibition with ruxolitinib decreased
kinase 1/2 (MEK1/2), but numerous ERK targets have been STAT3/5 signaling both in wild-type cells and those carrying
identified, including ELK-1, CREB, BCL2, Bad, FRAP1 (also JAKV617F. In the initial phase I/II study, the maximum tolerated
known as mTOR), and caspase 9, among numerous others. The dose was 25 mg when given twice daily and 100 mg on once-daily
activating effects of MEK1/2 on ERK are opposed by phosphatases dosing. After 3 months of therapy, 44% of patients with splenomegaly
that dephosphorylate and inactivate the enzyme (e.g., MAP kinase experienced a reduction of more than 50%. Responses were observed
phosphatase 1/2). in patients with the JAKV617F mutation as well as those with