1 research outputs found
Multidomain Targeting of Bcr-Abl by Disruption of Oligomerization and Tyrosine Kinase Inhibition: Toward Eradication of CML
The oncoprotein Bcr-Abl, the causative
agent of chronic myeloid
leukemia (CML), requires homo-oligomerization via a coiled-coil domain
to function [Bartram, C. R.; et al. <i>Nature</i> <b>1983</b>, <i>306</i> (5940), 277β280; and Zhao,
X.; et al. <i>Nat. Struct. Biol.</i> <b>2002</b>, <i>9</i>(2), 117β120]. While tyrosine kinase inhibitors
(TKIs) have shown great efficacy as treatment options for CML, their
use may cause an acquisition of mutations in the tyrosine kinase domain,
which prevent TKI binding and lead to a loss in activity [Woessner,
D. W.; et al. <i>Cancer J.</i> <b>2011</b>, <i>17</i>(6), 477β486]. Previously, we have shown that a
rationally modified coiled-coil domain (CC<sup>mut3</sup>) can disrupt
this oligomerization, inhibit proliferation, and induce apoptosis
in CML cells [Dixon, A. S.; et al. <i>Mol. Pharmaceutics</i> <b>2012</b>, <i>9</i>(1), 187β195]. Here,
we show that using the most recently approved TKI, ponatinib (Iclusig),
in combination with CC<sup>mut3</sup> allows a dose reduction of ponatinib
and increased therapeutic efficacy in vitro measured by reduction
in kinase activity, induction of apoptosis via caspase-3/7 and 7-AAD/Annexin
V assays, and reduced transformative ability measured by a colony
forming assay. The combination was effective not only in cells containing
wild-type Bcr-Abl (K562, Ba/F3-p210) but also cells with Bcr-Abl containing
the T315I mutation (Ba/F3-p210-T315I). In addition, we report for
the first time the ability of CC<sup>mut3</sup> alone to inhibit the
T315I mutant form of Bcr-Abl. This novel combination may prove to
be more potent than single agent therapies and should be further explored
for clinical use