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Cancer Drug Resist 2018;1:266-302 I http://dx.doi.org/10.20517/cdr.2018.18 Page 287

cells can utilise to survive and adapt to their adverse environmental conditions. Importantly, the UPR has
also been shown to be directly regulated by the androgen receptor, linking the UPR to the key oncogenic
driver of PCa. The aim of this project is to characterise UPR in PCa and to identify methods to target this
pathway and promote tumour death. In order to mimic the stressful conditions of the tumour microenvi-
ronment, Tunicamycin - a natural occurring antibiotic, was used to induce ER stress in four PCa cell lines
representing different stages of the disease (BPH-1, LNCaP, DU145 and PC3). Proliferation, as well as flow
cytometry assays, were used to study the effects of ER stress upon PCa cell proliferation, cell cycle and cell
death. Additionally, q-PCR analysis of downs-stream target genes was used to study the activation of the
UPR in response to ER stress. It has been found that ER stress reduces the proliferation of all PCa cells and
induces apoptosis. However, each cell line had a different sensitivity to ER stress. LNCaP cells were found
to be the most sensitive, having all three UPR arms active after 6 h of stress and displaying G1 cell cycle ar-
rest as well as high levels of apoptosis. DU145 had the highest apoptotic levels and the IRE1α arm activated
after 24 h of stress. BPH-1 and PC3 were less sensitive to ER stress, with BPH-1 having the lowest apoptotic
levels and no UPR arms being activated in PC3 after 24 h of stress. Further research will investigate the
effects of anti-androgens upon UPR signalling and characterise UPR target gene expression in response to
Tunicamycin and UPR inhibitors. Finally, UPR signalling will be manipulated in order to identify novel
therapeutic methods to treat therapy resistant disease.

39. Non-natural Macromolecules for new therapeutic strategies

2
1
Saeed Akkad , Michelle D. Garrett , Christopher J. Serpell 1
1 School of Physical Sciences, University of Kent, Canterbury, Kent CT2 7NH, UK
2 School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK

At the heart of biology are macromolecules with high-precision architectures - proteins and nucleic acids -
which are integral to all processes of life. Medicine can be viewed as a mission to modulate the activity of
these polymers. Historically, this has been achieved mainly using small molecules which bind to a specific
region of a biomacromolecule. However, biochemistry is replete with macromolecule-on-macromolecule
processes, pointing to alternative therapeutic strategies. To some extent this is reflected in the rise of bio-
pharmaceuticals (biologics) as medicines, but this neglects the potentially much greater chemical space
that is possible using non-natural macromolecules. Such species could be more highly tailored for certain
purposes, possess a much greater range of functionalities, be tuned for localisation, degradation, and im-
munogenicity, and could be made in scalable processes as used for other chemical entities. We are using
precision macromolecules to address cancer in two ways. In the first case, we are working to make the che-
mopreventive effects of non-steroidal anti-inflammatory drugs such as aspirin useful by creating nanocar-
riers which will direct them solely to cancer tissues. In the second approach, we are using a novel method
to generate sequence-defined non-natural polymers which undergo programmed folding and self-assembly,
analogous to proteins. These precision macromolecules are candidates for modulation of the most chal-
lenging oncogenic protein-protein interactions such as the RAS-RAF and MYC-MAX pairs. We are devel-
oping a chemical evolution strategy to identify binders of these proteins.

40. A combination of CDK4/6 and IGF-IR inhibitors induces synergistic growth inhibition of
human colorectal cancer cells with acquired resistance to anti-EGFR antibody

S. A. Khelwatty , S. Essapen , A. M. Seddon , Z. Fan , H. Modjtahedi 1
1,2
3
1
1
1 Kingston University London, School of Life Science, London, UK
2 Royal Surrey County Hospital, St Luke’s Cancer Centre, Guildford, UK
3 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston,
TX, USA