AURORA KINASES AS CANDIDATE TARGETS FOR T CELL ACUTE LYMPHOBLASTIC
LEUKEMIA TREATMENT
Cristina Prieto, Kris Jacobs, Olga Gielen, Patricia Altea, Sofie Demeyer, Sarah Provost and Jan Cools
VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium
Introduction and objectives
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive group of blood cancers resulting
from the transformation of hematopoietic progenitors and accounting for 10-15% of pediatric
and 25% of adult ALL cases. Although current treatment has improved T-ALL survival rates,
the response of adult and relapsed cases is still poor, prompting the need for new treatment
strategies. Aurora Kinases comprise a family of phosphoproteins performing multiple
functions in mitosis and meiosis and playing an essential role in cellular division by controlling
chromatid segregation. Overexpression or gene amplification of Aurora Kinases has been
reported in human cancers, being associated to poor prognosis. Nevertheless, the potential
of aurora kinase inhibitors (AKi) has not been addressed for T-ALL therapy. Here, we studied
the effects and mechanism of action of AKi on T-ALL.
Methods and Results
By a medium-throughput screen in vitro, validated by dose-response assays, we showed a
strong anti-leukemic effect of AKi on the vast majority of T-ALL cell lines tested, but we
distinguished a subset of resistant cells. RNA sequencing of responder and resistant cells
followed by GSEA revealed differences in various metabolic pathways including ROS and fatty
acid metabolism. DCFDA assays showed a good response to AKi relates to higher basal ROS
levels in T-ALL cells, which are further increased after exposure to the inhibitor.
Ferroptosis is a recently described form of programmed cell death characterised by the
accumulation of lipid ROS, whose regulatory role in tumorigenesis has been reported,
although this mechanism is still not understood and it has not been widely studied in T-ALL.
Using the lipid peroxidation sensor Bodipy-C11, we observed increased ferroptosis on
responder cells after AKi exposure, and this effect was prevented by co-treatment with a lipid
peroxidation inhibitor. We also observed overexpression of pro-ferroptotic genes (VDAC3,
ACSL4 and Sat1) and downregulation of anti-ferroptotic genes (GPC4, FTL and FSP1) in
responder cells after AKi treatment. Polyunsaturated fatty acids (PUFAs) are sensitive to lipid
peroxidation, and they have been previously described to increase ferroptosis on
hematological malignancies. Similarly, we have observed that resistant cells can be sensitized
to AKi by PUFAs exposure, supporting the role of ferroptosis in T-ALL response to AKi.
A metabolic profiling revealed higher polar metabolites and fatty acid abundancies when
resistant cells were exposed to AKi, while responder cells derive more glucose carbons to fatty
acid synthesis. These observations suggest that responder cells are more dependent on lipid
biosynthesis, which entails higher need of NADPH availability, and thus these cells present less
antioxidant capacity to combat ROS efficiently. On the other hand, resistant cells show higher
fatty acid intake, leaving more NADPH available for ROS scavenge and showing lower ROS
levels. Supporting this hypothesis, we were able to sensitize resistant cells to AKi by fatty acid
deprivation.
Conclusions
Together, these data identify aurora kinases as potential targets for T-ALL treatment. We hint
at lipid ROS-driven ferroptosis as the mechanism mediating the effect of AKi on T-ALL cells,
and suggest different strategies to avoid potential resistance to AKi in the clinic.
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