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Cancer Drug Resist 2018;1:266-302 I http://dx.doi.org/10.20517/cdr.2018.18 Page 281

Chronic myeloid leukaemia (CML) is associated with the BCR-ABL1 (BA) oncogene and managed with
drug therapy [Imatinib (IM)]. However, 20% of patients will develop drug resistance resulting in fatality
within 12 months. Previous work in the lab had established a preclinical model of CML drug resistance
using KCL22 cells. By gradually exposing these cells to increasing concentrations of IM, a drug-resistant
derivative (IMr) was established. The IMr cells recapitulated clinical observations where drug treatment
ablated the activity of BA yet they continue to grow. In order to survive the IMr cells must acquire new
oncogenic drivers that compensate for the loss of BA. Research focused on the functional requirement
of the SOX4 factor in establishing the IMr phenotype. Depletion of SOX4 within the IMr cells inhibited
cell growth. Interestingly, the complimentary gain-of-function studies failed to generate SOX4-expressing
KCL22 stables. Targeting SOX4 with the aim of restoring its normal functional activity holds great promise
for the therapeutic treatment of drug-resistant CML.

30. PHLDA1 downregulation mediates drug resistance in receptor tyrosine kinase-driven
cancer and can be modulated using HDAC Inhibitors

2
3
1
1
N. S. Clayton , E. P. Carter , A. E. Fearon , J. A. Heward , R. P. Grose 1
1 Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of
London, London EC1M 6BQ, London, UK
2 Inst. f. Molecular Health Sciences, Department of Biology, ETH Zürich, Zürich 8093, Switzerland
3 Centre for Haemato-Oncology, Barts Cancer Institute, London EC1M 6BQ, UK

Development of resistance causes failure of drugs targeting oncogenic receptor tyrosine kinases (RTKs)
and represents a critical challenge for precision medicine. Here, we show that transcriptional downregula-
tion of the PH domain-containing protein PHLDA1 is critical to the acquisition and maintenance of drug
resistance in RTK-driven cancer. Using resistance to fibroblast growth factor receptor - targeted therapy
as a model, we identified an Akt-driven compensatory mechanism underpinned by downregulation of
PHLDA1. We demonstrate broad clinical relevance of our findings, showing that PHLDA1 downregulation
also occurs in response to RTK-targeted therapy in breast and renal cancer patients. Crucially, knockdown
of PHLDA1 alone was sufficient to confer de novo resistance to RTK inhibitors in vitro and induction of
PHLDA1 expression re-sensitized drug-resistant cancer cells to targeted therapies. This identifies PHLDA1
as a biomarker for drug response and highlights the potential of PHLDA1 reactivation as a means of cir-
cumventing resistance to RTK inhibitors. We have identified inhibition of the MAPK pathway as a crucial
step in PHLDA1 downregulation and show that ERK1/2 inhibition produces significant epigenetic changes
at the PHLDA1 locus, specifically, a decrease in the activatory marks H3Kme3 and H3K27ac. In line with
this, we show that treatment with clinically relevant Class I HDAC inhibitors restores PHLDA1 expression
+
in resistant cells. Using HER2 breast cancer cells as a model system, we have shown that HDAC inhibitors
increase the sensitivity of resistant cells to HER2 -targeted therapy and when given in combination with
+
lapatinib, produce a synergistic effect on cell growth in parental cell populations.

31. Elucidating mechanisms of resistance to PI3K inhibition in pancreatic cancer using
functional genomics and combinatorial drug screening

1
1
2
Charlotte Milton , Annette Self , Rosemary Burke , Federica Piccioni , David Root , Steven R.
1
2
Whittaker 1
1 Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK
2 Genetic Perturbation Platform, The Broad Institute, Cambridge, MA, USA
Activating mutations in the oncogene KRAS are present in 95% of pancreatic ductal adenocarcinoma