Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

170 Applying Pharmacogenomics in Therapeutics
A NEW GENERATION OF THE BCR-ABL TKIs
As the first member of targeted therapy for cancers, imatinib (Gleevec; www.
gleevec.com) has revolutionized the therapy of CML for over a decade by binding
to the inactive configuration domain of bcr-abl kinase and competitively inhibiting
the ATP-binding site of bcr-abl kinase. The bcr-abl kinase is a constitutively active
product of BCR-ABL fusion gene resulted from reciprocal translocation between
chromosomes 9 and 22, which is also known as Philadelphia translocation. BCR-
ABL is usually associated with CML (95% of CML patients have this abnormality)
and a subset of ALL. Imatinib is also a potent inhibitor of tyrosine kinase derived
from c-Kit. Other than Philadelphia chromosome-positive CML, FDA also approved
imatinib for the c-Kit positive (CD117) GIST and aggressive systemic mastocytosis
(ASM) without D816V c-Kit mutation (or c-Kit mutation status unknown) based on
the PGx studies. 8
Although imatinib is effective in treating CML, about one-third of CML patients
developed to be imatinib resistant due to primary resistance or secondary resistance.
Primary resistance is defined as initial lacking of response due to low imatinib plasma
concentration resulting from low activity of the human OCT1 and/or overexpression
of multidrug resistance–associated protein 1 (MRP1, encoded by ABCC1). Secondary
resistance to imatinib is most commonly caused by acquired bcr-abl kinase domain
mutations, which account for 40–90% of patients with imatinib resistance. More
than 100 point mutations in the BCR-ABLE fusion gene lead to single amino acid
substitution and also result in resistance through a variety of mechanisms, including
ATP phosphate binding loop (P-loop), catalytic domain, ATP-binding site, or activation
loop conformational change. 105 The second- generation bcr-abl TKIs, such as
dasatinib, nilotinib, bosutinib, and ponatinib, are able to overcome the majority of
the secondary resistance to imatinib. Like imatinib, nilotinib also binds to the inactive
conformation domain of bcr-abl kinase. Therefore, nilotinib is not the best alternative
treatment for most imatinib-resistant mutations. On the other hand, the novel
small molecular TKI dasatinib binds to the kinase domain in the open conformation,
which is different from the mechanism of imatinib and nilotinib. Thus, dasatinib can
be reserved for CML patients who are resistant to imatinib and nilotinib. However,
T315I mutation confers resistance to imatinib, dasatinib, nilotinib, and bosutinib.
Fortunately, the T315I mutation is sensitive to ponatinib treatment. 106,107
In recent years, there have been more developments of therapies that target
the Philadelphia chromosome. These two new therapies are indicated for CML
patients who are Ph+. Bosutinib (Bosulif ® ) is a TKI that targets Philadelphiapositive
CML patients, and TKIs’ function as a switch for many cellular activities.
Bosutinib inhibits the BCR-Abl kinase and also the Src-family kinases. Bosutinib
is indicated for the treatment of patients with chronic, accelerated, or blast phase
Philadelphia-positive CML with resistance or intolerance to prior therapy. Prior
therapy is defined as therapy with imatinib, dasatinib, and nilotinib. Bosutinib has
no activities against the T315I and V299L mutant cells. 108 Ponatinib (Iclusig ® ) is
a protein inhibitor of Bcr-Abl and Src. Ponatinib is indicated for the treatment of
patients with chronic phase, accelerated phase, or blast phase CML that is resistant
or intolerant to prior TKI therapy or Philadelphia-positive ALL that is resistant or