NcXHF

MICHAEL W. DEININGER
the ATP-binding loop, preventing the rearrangements required
for optimal drug binding. Examples include
Q252H, Y253(H/F), and E255(K/V). Last, mutations in
the activation loop such as H396P stabilize an open conformation,
to which imatinib cannot bind. 23 Although
imatinib is vulnerable to a broad range of mutations, the
spectrum is much more limited for nilotinib and dasatinib,
reflecting their greater potency and, in the case of
dasatinib, less stringent binding requirements. 24 Clinical
resistance mutations are precisely predicted by in vitro assays,
which enable the development of preemptive strategies
to overcome this type of resistance. 25-27 Mutation
testing is recommended upon disease progression and if
milestones are not met. Most laboratories use Sanger sequencing,
which has a sensitivity of approximately 20%
mutant allele. This level of sensitivity seems to provide the
right balance between sensitivity and specifıcity. More
sensitive assays such as next-generation sequencing are
under development and may replace Sanger sequencing in
the future. Biochemical and cell proliferation data have
been used to rank kinase domain mutations according to
the degree of TKI resistance they confer. 28 Although these
data are based on in vitro studies, they tend to correlate
with clinical responses. 29,30 However, correlations are not
as tight as one might suspect, suggesting that additional
mechanisms govern clinical resistance. The exception to
this rule is the T315I mutation that confers complete resistance
to all approved TKIs, except ponatinib. For several
other mutants, the difference in sensitivity is suffıcient
to support the use of dasatinib over nilotinib, or vice versa
(Fig. 1). An in-depth discussion of the many reported mutations
and their sensitivity profıles is beyond the scope of
this chapter and the reader is referred to detailed reviews
of this subject. 31-33
Activation of Alternative Signaling Pathways
In contrast to kinase domain mutations, BCR-ABL1 kinase–independent
resistance is less well understood and
seems to involve multiple different mechanisms. For example,
activation of SRC family kinases, MAP kinase,
STAT5, SYK, and PI3K have all been associated with TKI
resistance, despite sustained inhibition of BCR-ABL1. 34-38 Extrinsic
factors such as cytokines may also play a role. 39,40 Targeting
these diverse pathways is therapeutically challenging and
common downstream effector molecules such as pSTAT3 or
processes such as nuclear cytoplasmic transport may be more
promising. 41-43
FIGURE 1. Activity of Imatinib, Bosutinib, Dasatinib, Nilotinib, and Ponatinib against Mutated Forms of BCR-ABL1
Cell proliferation IC 50 values of the indicated TKIs are shown against BCR-ABL1 single mutants. The color gradient demonstrates IC 50 sensitivity for each TKI relative to its activity against cells
expressing native BCR-ABL1. Note that clinical activity is also dependent on additional factors, such as drug concentrations achieved in the plasma of patients.
Adapted with permission from Redaelli et al. 64
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