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Cancer Drug Resist 2018;1:266-302 I http://dx.doi.org/10.20517/cdr.2018.18 Page 291

Current treatment strategies for non-metastatic localised prostate cancer patients classified as “high risk”
rely upon either radical prostatectomy or radiotherapy followed by androgen deprivation therapy. De-
spite these interventions, a significant proportion of patients with high-risk disease acquire resistance
and progress with metastasis which will ultimately result in death. Increasing evidence suggests that a
small population of tumour-initiating cells, cancer stem cells (CSCs), are responsible for this progression
and are capable of evading, or are refractory to, standard therapies. Targeting CSCs therefore offers an
interesting therapeutic strategy which should offer more sustained responses to treatment. We have re-
cently shown that inhibiting the anti-apoptotic protein cFLIP in breast cancer cells dramatically sensitizes
CSCs to the targeted apoptotic agent TRAIL, resulting in a profound decrease in experimental metastasis.
cFLIP is overexpressed in localized high-grade prostate tumours, and as these tumours are associated
with increased-risk of metastasis, we hypothesize that cFLIP may play a similar role in the maintenance
of CSCs in prostate cancers. Using a novel pharmacological inhibitor of cFLIP (OH14) developed in our
laboratory we have confirmed that cFLIP suppression combined with TRAIL treatment selectively targets
prostate CSCs in both established and patient derived cultures. Furthermore, OH14 alone has shown efficacy
as a monotherapy at reducing bulk cell viability in low grade primary prostate cancers. Interestingly, we have
found cFLIP to be overexpressed in the metastatic subline PC-3M, with OH14 and TRAIL treatment signifi-
cantly reducing bulk and CSC activity in these cells. We are now utilising orthotopic models of metastatic dis-
ease as well as developing a variety of PDX models to investigate how this combination acts in vivo whilst
also investigating the role of cFLIP in models of acquired resistance to both docetaxel and enzalutamide in
vitro. We believe that this CSC-based therapeutic intervention may have the potential to halt the spread of
disease and prevent recurrence in high-risk patients, which no current treatment option is able to do.

46. Chronic Myeloid Leukaemia Resistance to Therapy: running on RUNX1

Naomi Gibson, Geetha Bheeshmachar, Peter Laslo

Faculty of Medicine and Health, University of Leeds, St James’s Hospital, Leeds, UK

Chronic Myeloid Leukaemia (CML) is associated with the BCR-ABL1 (BA) tyrosine kinase oncogene and
managed with drug therapy [Imatinib (IM)]. However, 20% of patients develop drug resistance, resulting
in fatality within 18 months. A preclinical model of IM resistance using a CML cell line (KCL-22 cells)
established that IM resistant (IMr) cells are kinase independent, recapitulating clinical observations where
treatment inhibits BA activity yet the cells continue to survive. Therefore, the IMr cells must acquire new
oncogenic drivers that compensate for the loss of BA activity. Gene expression analysis revealed that > 1,400
genes are differentially regulated in IMr cells. Among these genes, the haematopoietic transcription factor
RUNX1 was of particular interest, being dysregulated in multiple haematological malignancies. RUNX1
expression is upregulated upon IM resistance in CML patients and our pre-clinical model, and RUNX1
protein is highly induced in the IMr cells. Knockdown of RUNX1 using two different siRNA constructs
caused growth inhibition of IMr cells. Further analysis revealed that RUNX1 depletion induced a macro-
phage-like morphology of IMr cells and the upregulation of myeloid-associated genes including CD11b and
MCSF-R, suggesting that RUNX1 depletion results in partial differentiation of IMr cells. Pharmacological
inhibition of RUNX1 activity replicated these results, highlighting its potential as a therapeutic target.

47. Downregulation of SLFN11 confers resistance to DNA damaging agents; insights into
resensitization with novel DNA damage response inhibitor combinations

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Claudia Winkler , Tarrion Baird , Michael P. Menden , Jenni Nikkilä , Martine P. Roudier ,
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Gemma N. Jones , Andrew J. Pierce , Mark O’ Connor , Elisabetta Leo 1
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