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YM155 potently kills acute lymphoblastic leukemia cells through activation of the DNA damage pathway
Bill H Chang1,2, Kara Johnson3, Dorian LaTocha4
1Division of Pediatric Hematology and Oncology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, 97239, USA. changb@ohsu.edu.
Background:
Novel-targeted therapies are in rapid development for the treatment of acute lymphoblastic leukemia (ALL) to overcome resistance and decrease toxicity. Survivin, a member of the inhibitor of apoptosis gene family and chromosome passenger complex, is critical in a variety of human cancers, including ALL. A well-established suppressor of survivin has been the small molecule, YM155. Reports are identifying other mechanisms of action for YM155. Therefore, we sought to investigate the mode of action and role of YM155 for therapeutic use in the context of ALL.
Methods:
Primary ALL samples and ALL cell lines were interrogated with YM155 to identify drug sensitivity. Ph(+)ALL harboring the BCR-ABL1 oncogene were tested for any interaction with YM155 and the multi-kinase inhibitor dasatinib. Representative ALL cell lines were tested to identify the response to YM155 using standard biochemical assays as well as RNA expression and phosphorylation arrays.
Results:
ALL samples exhibited significant sensitivity to YM155, and an additive response was observed with dasatinib in the setting of Ph(+)ALL. ALL cells were more sensitive to YM155 during S phase during DNA replication. YM155 activates the DNA damage pathway leading to phosphorylation of Chk2 and H2AX. Interestingly, screening of primary patient samples identified unique and exquisite YM155 sensitivity in some but not all ALL specimens.
Conclusion:
These results are the first to have screened a large number of primary patient leukemic samples to identify individual variations of response to YM155. Our studies further support that YM155 in ALL induces DNA damage leading to S phase arrest. Finally, only subsets of ALL have exquisite sensitivity to YM155 presumably through both suppression of survivin expression and activation of the DNA damage pathway underscoring its potential for therapeutic development.
Insights
YM155 shows promise in treating acute lymphoblastic leukemia (ALL) by inducing DNA damage and S phase arrest. Patient sample screening reveals varied sensitivity, highlighting YM155
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Acute lymphoblastic leukemia (ALL) treatment faces challenges with drug resistance and toxicity.
- Survivin, a key protein in ALL, is a target for novel therapies.
- YM155, a small molecule, is known to suppress survivin and has other potential mechanisms.
Purpose of the Study:
- To investigate the mechanism of action of YM155 in ALL.
- To evaluate the therapeutic potential of YM155 in ALL.
- To identify patient subgroups with specific sensitivity to YM155.
Main Methods:
- Sensitivity of primary ALL samples and cell lines to YM155 was assessed.
- Interaction of YM155 with dasatinib in Ph(+)ALL was tested.
- Biochemical assays, RNA expression, and phosphorylation arrays were used to analyze YM155 response.
Main Results:
- ALL samples demonstrated significant sensitivity to YM155.
- YM155 induces DNA damage, leading to Chk2 and H2AX phosphorylation and S phase arrest.
- A subset of primary ALL samples showed unique and exquisite sensitivity to YM155.
Conclusions:
- YM155 induces DNA damage and S phase arrest in ALL cells.
- Individual variations in YM155 response were identified across primary patient samples.
- YM155 shows therapeutic potential in ALL, particularly in subsets with exquisite sensitivity.
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