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Printable Handouts
Navigable Slide Index
- Introduction
- Mechanisms of TKI resistance
- Mutations in patients with Imatinib resistance
- Imatinib binds an inactive conformation of ABL1
- How do mutations cause drug resistance?
- Steric hindrance: BCR-ABL1(T315I)
- ABL1 kinase inhibitors
- Binding of Nilotinib to ABL1
- Dasatinib binds an active conformation of ABL1
- CML-CP: survival on Dasatinib
- Accelerated mutagenesis screen
- Mutagenesis assay with 100nM Dasatinib
- BCR-ABL1(T315I): default in 2nd-generation TKIs
- Resistance due to BCR-ABL1 point mutations
- Ponatinib skirts BCR-ABL1(T315I)
- Mutation screening in a T315I background
- Ponatinib phase 2 study: results in CML-CP
- Ponatinib phase 2: OS in BP-CML and Ph+ ALL
- Ponatinib resistance
- T315I compound mutations confer TKI resistance
- Rationalizing resistance due to E255V/T315I
- Mechanisms of TKI resistance
- BCR-ABL1 kinase independent resistance
- pSTAT3(Y705) is activated in CML CD34+ cells
- Remaining challenges
- Quiescent CML cells survive in Imatinib presence
- Imatinib inhibits BCR-ABL1 in CML progenitor cells
- Imatinib inhibits BCR-ABL in quiescent Lin- cells
- Inhibition of BCR-ABL restores normal growth
- Alternative pathways in CML LSC
- Remission after Imatinib discontinuation
- MMR after Imatinib discontinuation (1)
- MMR after Imatinib discontinuation (2)
- CML extinction by attrition?
- Summary (1)
- Summary (2)
Topics Covered
- Mechanisms of resistance to tyrosine kinase inhibitors (TKIs)
- Overcoming resistance with second and third generation TKIs
- Remaining difficulties in eradicating CML
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Deininger, M.W. (2015, September 30). CML: genetic paradigm of targeted therapy 2 [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 3, 2024, from https://doi.org/10.69645/HGKD8551.Export Citation (RIS)
Publication History
Financial Disclosures
- Prof. Michael W. Deininger has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
CML: genetic paradigm of targeted therapy 2
Published on September 30, 2015
35 min
Other Talks in the Series: Cancer Therapies in the Personalized Medicine Era
Other Talks in the Series: Cancer Genetics
Transcript
Please wait while the transcript is being prepared...
0:00
MICHAEL DEININGER: Hello,
this is Dr. Michael Deininger.
I'm the division
chief for Hematology
and Hematologic Malignancies
at the University of Utah,
Huntsman Cancer Institute.
We continue our discussion of
chronic myeloid leukemia, or CML.
The second part of
the presentation will
cover topics of imatinib
resistance, second and
third generation tyrosine
kinase inhibitors,
and minimal residual disease in CML.
0:28
Now, let's look at the
question of imatinib resistance.
This Western blot shows
you cells from a CML patient,
analyzed for
phosphorylation of CrkL,
which is a substrate of BCR.
The lower band in
these Western blots
is the non-phosphorylated
form and the upper band
is the phosphorylated form.
What you predict with
tyrosine kinase inhibitor
is that the upper
band will disappear
completely, because only the
non-phosphorylated protein
will remain.
However, if you look
at the middle panel,
even in the presence of
1 micromole of imatinib,
the phosphorylation is
completely preserved.
That indicates that
BCR-ABL signaling
has been reactivated at the time
of this resistance development.
And in this particular patient, that
turned out to be due to a mutation
in the BCR-ABL kinase domain.
In contrast, if you
look at the right slide,
the situation is very different.
Despite the resistance, clinically
there is a complete predominance
of the non-phosphorylated
form of CrkL,
indicating that BCR-ABL kinase
activity remains suppressed,
and yet the disease
has become resistant,
suggesting that another pathway has
been activated to replace BCR-ABL.