CLINICAL NEWS
BCR-ABL1 Inhibitor Axitinib Overcomes
Drug Resistance in CML
While selective BCR-ABL tyrosine kinase
inhibitors (TKIs) have markedly improved outcomes for patients with chronic
myeloid leukemia (CML), they are not as
effective in patient who carry the BCRABL1 (T315I) mutation, whose disease
is often resistant to treatment. According
to results reported in a research letter
published in Nature, though, patients may
have a new therapy option with axitinib,
a vascular endothelial growth factor
receptor (VEGFR) inhibitor previously
approved for second-line treatment of
advanced renal cell carcinoma.
Tea Pemovska, MD, and colleagues,
reported that axitinib inhibited the BCRABL (T315I) mutation in samples from
patients with CML and Philadelphia chromosome–positive B-cell acute lymphocytic leukemia (Ph+ ALL). According to the
authors, this was an “unexpected” finding,
and one that brings hope to patients with
drug-resistant CML and Ph+ B-cell ALL.
“Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug
approved for renal cancer, as an inhibitor
for ABL1 gatekeeper mutant drug-resistant leukemia patients,” the authors wrote.
The only other approved treatment option
for these patients is the ABL1 inhibitor
ponatinib, which has toxicity limitations.
To determine axitinib’s efficacy in
this population, Dr. Pemovska, from the
University of Helsinki in Finland, and her
team examined cancer cells ex vivo from
patients with T315I CML and B-ALL who
had developed resistance to currently
available treatments.
Using phenotypic drug sensitivity and
resistance testing, they determined the
growth response of the cells to a panel
of 252 drugs (125 already approved and
127 investigative). As they expected, the
growth of T315I cancer cells was inhibited
by ponatinib and drugs that targeted mol-
ecules downstream of BCR-ABL signaling,
but not by imatinib, nilotinib, or dasatinib,
the most commonly used TKIs for patients
with CML or Ph+ ALL.
The authors pointed out that the kinase
activity of the T315I mutation was inhibited at a very low concentration of axitinib
(100 nM), which compared favorably with
the concentration required to inhibit the
tyrosine kinase activity of VEGFR (20
nM). The activity of wild-type BCR-ABL
kinase was inhibited with a significantly
higher concentration of axitinib (3800
nM) – suggesting that axitinib specifically
and potently inhibits BCR-ABL (T315I).
Dr. Pemovska and colleagues then
tried to determine how the VEGFR inhibitor was active in inhibiting BCR-ABL1
(T315I). Compared with other BCR-ABL
kinase inhibitors (like imatinib and dasatinib), axitinib was shown to fill different
binding spaces – making the bond to the
T3151 protein tighter.
Germline Mutation in Leukemia Highlights
Disease Complexity
A recent report published in Nature
Genetics has underscored the key role that
the ETV6 gene plays in platelet formation
and leukemia predisposition.1 Researchers
pinpointed the gene as a tumor suppressor
in childhood leukemia and identified a
trio of ETV6 germline mutations that may
contribute to thrombocytopenia, high red
blood cell mean corpuscular volume, and
leukemia predisposition.
While this research is not the first to
find germline mutations in leukemia –
investigators at St. Jude Children’s Research
Hospital recently identified the PAX5
mutation,2 and investigators at Cleveland
Clinic the DDX41 mutation3 – it raises
the notion that leukemia is a much more
complex entity than we currently think it is,
corresponding author Jorge Di Paola, MD,
explained to ASH Clinical News.
What is the main take-home message
of the study? “There might be more to
the malignant transformation of the bone
marrow than we realize,” said Dr. Di Paola, of
the University of Colorado Anschutz Medical
Campus (AMC) in Aurora, Colorado. “Now
that we’ve discovered these mutations, there
are databases out there with tons of families
in them with these germline mutations, so I
hope institutions check for them.”
ASHClinicalNews.org
In the current study, lead author Leila
Noetzli, a PhD candidate at AMC, and
colleagues screened 23 families, eventually
identifying one with autosomal dominant
thromboc ]