Nilotinib and MEK Inhibitors
Induce Synthetic Lethality
through Paradoxical Activation
of RAF in Drug-resistant CML
Chronic myeloid leukemia (CML)
is characterized by the presence
of the Philadelphia chromosome,
a chromosome 9/chromosome 22
translocation that fuses BCR
(encoding breakpoint cluster
region) to ABL, which encodes
the Abelson tyrosine kinase. The
RAS/RAF/MEK/ERK pathway promotes
CML cell survival. Under some
circumstances, RAF inhibitors
drive paradoxical activation of
BRAF and CRAF to accelerate
tumorigenesis by hyperactivating
MEK and ERK. Acquired drug
resistance through BCR–ABL–dependent
and BCR–ABL–independent
mechanisms is thus a persistent
problem for the treatment of CML.
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In a recent study published in
Cancer Cell, Packer et al.
investigated whether other kinase inhibitors can also drive
paradoxical activation of RAF,
MEK, and ERK and investigated
the underlying mechanisms and
potential clinical consequences.
They showed that some frontline
CML drugs such as imatinib,
nilotinib, and dasatinib possess
weak off-target activity against
RAF and, therefore, drive
paradoxical activation of BRAF
and CRAF in a RAS-dependent
manner. Critically, because RAS
is activated by BCR–ABL, in
drug-resistant CML cells, RAS
activity persists in the
presence of these drugs, driving
paradoxical activation of BRAF,
CRAF, MEK, and ERK and leading
to an unexpected dependency on
the pathway. Consequently,
nilotinib synergizes with MEK
inhibitors to kill
drug-resistant CML cells in
vitro and block tumor growth in
mice.
This study showed that
paradoxical activation of BRAF
and CRAF can drive unexpected
biological responses in CML and
has uncovered a synthetic lethal
interaction that can be used to
kill drug-resistant CML cells in
vitro and in vivo. This provides
an intriguing strategy that may
prevent the emergence of
drug-resistant clones in
patients with CML.
Source:
Cancer
Cell. 2011;20:715 – 727
SB1518, a Novel Macrocyclic
Pyrimidine-based JAK2 Inhibitor,
for the Treatment of Myeloid and
Lymphoid Malignancies
The Janus kinase (JAK) family of
tyrosine kinases has important
roles in the cellular signaling
pathways that control
proliferation, differentiation,
and cell death. FLT3 (FMS-like
tyrosine kinase-3) belongs to a
family of class III receptor
tyrosine kinases, and it is the
most frequently mutated gene in
acute myeloid leukemia, leading
to poor prognosis in some
patients. JAK2 and FLT3 offer
hope as novel targets for the
development of innovative
therapies. Macrocyclic organic
compounds in general constitute
a structural class that
possesses immense potential for
pharmacological applications,
but their utility has not been
fully exploited because of the
synthetic challenges and
concerns over apparent lack of “druglikeness.”
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Hart et al. recently reported in
Leukemia the structure and
pharmacological profile of SB1518, a
novel pyrimidine-based,
low-molecular-weight macrocycle with
selective potent inhibitory activities
against JAK2 and FLT3. SB1518 exhibits
favorable pharmaceutical properties and
shows efficacy in cellular and animal
models of hematological malignancies as
well as primary cells derived from
patients with myeloproliferative
disease. The agent shows potent effects
on cellular JAK–STAT pathways,
inhibiting tyrosine phosphorylation on
JAK2 (Y221) and downstream STATs. As a
consequence, SB1518 has potent anti-proliferative
effects on myeloid and lymphoid cell
lines driven by mutant or WT JAK2 or
FLT3, resulting from cell cycle arrest
and induction of apoptosis. SB1518
inhibits intra-tumor JAK2/STAT5
signaling in a dose-dependent manner,
leading to tumor growth inhibition in a
subcutaneous model generated with SET-2
cells derived from a JAK2V617F patient
with megakaryoblastic leukemia.
Moreover, SB1518 is active against
primary erythroid progenitor cells
sampled from patients with
myeloproliferative disease.
This study reveals a novel chemical
entity selective for JAK2 over JAK1 and
JAK3 with additional activity against
FLT3. It is efficacious against cell
lines dependent on constitutively active
or ligand-activated JAK2 and FLT3
signaling and effectively blocks STAT
signaling in these cells. SB1518’s
favorable pharmaceutical and
pharmacological properties provide a
rationale for clinical development in
multiple myeloid and lymphoid disease
indications.
Source:
Leukemia.
2011;25(11):1751–1759
SF3B1
and
Other Novel Cancer Genes in Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is an
incurable disease characterized by
extensive clinical heterogeneity despite
a common diagnostic immunophenotype
(surface expression of CD19+, CD20+dim,
CD5+, CD23+, and sIgMdim). The ability
to predict a more aggressive disease
course has improved with the use of
tests for biologic markers (degree of
somatic hypermutation in the variable
region of the immunoglobulin heavy chain
[IGHV] gene and expression of ZAP70) and
the detection of cytogenetic
abnormalities (deletions in chromosomes
11q, 13q, or 17p and trisomy 12).
Despite these advances, prediction of
the disease course is not highly
reliable.
In a recent study published in NEJM,
Wang et al. obtained DNA samples from
leukemia cells in 91 patients with CLL
and performed massively parallel
sequencing of 88 whole exomes and whole
genomes, together with sequencing of
matched germline DNA, to characterize
the spectrum of somatic mutations in
this disease. Nine genes mutated at
significant frequencies were identified,
including four with established roles in
CLL (TP53 in 15% of patients, ATM in 9%,
MYD88 in 10%, and NOTCH1 in 4%) and five
with unestablished roles (SF3B1, ZMYM3,
MAPK1, FBXW7, and DDX3X). SF3B1, which
functions at the catalytic core of the
spliceosome, was the second most
frequently mutated gene (with mutations
occurring in 15% of patients). SF3B1
mutations occurred primarily in tumors
with deletions in chromosome 11q, which
are associated with a poor prognosis in
patients with CLL.
Research findings regarding SF3B1
mutations and identification of coding
mutations in CLL can lead to the
development of mechanistic hypotheses,
novel prognostic markers, and potential
therapeutic targets.
Source:
N Engl J Med.
2011;365(26):2497–2506
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