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CANCER STEM CELLS AND
ONCOLOGY RESEARCH
11
th
International Conference on
Journal of Medical Oncology and Therapeutics
|
Volume 3
Manic Gwenola et al., J Med Oncl Ther 2018, Volume 3
TARGETING CHK1 FOR ERADICATING
COLORECTAL CANCER STEM CELLS
Manic Gwenola
1
, Sistigu A
1,2
, De Maria R2
and
Vitale I
1,3
1
Regina Elena National Cancer Institute, Italy
2
Institute of General Pathology, Catholic University “Sacro Cuore”, Rome, Italy
3
Department of Biology, University of Rome “Tor Vergata”, Rome, Italy
T
he tumor is a dynamic system composed by heterogeneous
populations of cells with cancer stem cells (CSCs) at its apex. CSCs
drive tumor development and progression, and their efficient targeting
is required for tumor eradication. Here, with the aim at identifying novel
CSC-targeting strategies, we generated a panel of ~30 CRC patient-
derived tumorspheres enriched for CSCs (CRC-SCs). By performing a
drug-library screening with a panel of clinically-relevant drugs on CRC-
SCs, we identified LY2606368 as a potent anti-CSC agent. Thereafter,
we confirmed that LY2606368 was able to kill CSCs from a significant
number of patients (~36%), both
in vitro
and
in vivo
. As for its mechanism
of action, we demonstrated that LY2606368 inhibits CHK1 leading to
perturbation of DNA replication followed by premature mitosis entry
and cell death of DNA-damaged cells. Moreover, through (cyto)genetic
and phosphoproteomic analyses, we provided evidence that LY2606368-
sensitive CRC-SCs display ongoing replication stress response
associated with mutation(s) in TP53 and hyperdiploidy. This made these
CRC-SCs highly dependent on CHK1 function. Accordingly, experimental
increase of endogenous DNA damage or cell ploidy sensitized formerly
resistant CRC-SCs to LY2606368. This study provides a strong rationale
for biomarker-driven clinical trials with LY2606368 in CRC patients.
Gwenola Manic received her PhD in 2012 for
studying the impact of DNA repair on viral ex-
pression. During her first post-doc in Rome she
investigated the role of chromosomal instabili-
ty and replication stress in CSCs and identified
CHK1 as a target for eradicating CSCs in col-
orectal tumors (Gut 2017, Mol Cell 2017). She
is now working as a senior scientist on a project
investigating the replication stress response in
CSCs and the link between chromosome insta-
bility and immunogenic potential of CSCs. She
is in the editorial board of Frontiers in Oncology.
She is author of 26 ISI papers (including Sci-
ence, Mol Cell and Gut).
gwenola.manic@gmail.comBIOGRAPHY