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Cancer Drug Resist 2018;1:266-302 I http://dx.doi.org/10.20517/cdr.2018.18 Page 279

beamformers; each is tailored to a particular region in the space and resistant to interference effects origi-
nating from other regions. The new approach attempts to explore the maximum amount of variation in the
data with a small number of principal variables. Through simulation studies, we show that it substantially
outperforms the existing methods in terms of sensitivity and specificity. We apply the proposed method
to IC cancer drug and gene expression datasets, identifying a set of important genes co-associated with a
50
group of cancer drugs.

26. Targeting of a transcriptional state implicated in resistance to MEK inhibition in KRAS-

mutant colorectal cancer

2
1
1
Steve Wagner , Georgios Vlachogiannis , Alexis De Haven Brandon , Melanie Valenti , Gary
1
1
3
1
4
1
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Box , Liam Jenkins , Caterina Mancusi , Annette Self , Floriana Manodoro , Ioannis Assiotis ,
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4
Penny Robinson , Ritika Chauhan , Alistair G Rust , Nik Matthews , Kate Eason , Khurum
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Khan , Naureen Starling , David Cunningham , Anguraj Sadanandam , Clare M. Isacke , Vladimir
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Kirkin , Nicola Valeri , Steven R. Whittaker 1
1
1 Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK
2 Division of Molecular Pathology, The Institute of Cancer Research, London, UK
3 Breast Cancer Now Research Centre, The Institute of Cancer Research, London, UK
4 Tumour Profiling Unit, The Institute of Cancer Research, London, UK
5 Department of Medicine, Royal Marsden NHS Foundation Trust, London, UK
The MEK inhibitor (MEKi) trametinib has shown clinical benefit in BRAF-mutant melanoma but showed
no clinical responses in KRAS-mutant colorectal cancer. To gain insight into potential mechanisms of
resistance, we used a pharmacogenomics analysis of colorectal cancer cell lines exhibiting differential sen-
sitivity to MEK inhibition. Strikingly, we identified a transcriptional state, involving increased interferon
and inflammatory gene expression, to be highly enriched in cell lines displaying intrinsic and acquired
resistance to MEK inhibition. Inhibition of this transcriptional state was achieved by small molecule inhi-
bition of the bromodomain family of proteins, which suppressed interferon and inflammatory gene expres-
sion and restored sensitivity to MEK inhibition. The combination of the bromodomain inhibitor JQ1 and
trametinib showed synergistic anti-proliferative effects and induced apoptosis in MEKi-resistant colorectal
cancer cell lines. Elevated expression of interferon/inflammatory genes was observed in patient-derived or-
ganoid models which were also resistant to trametinib and were resensitized by co-treatment with JQ1. In
both xenograft and syngeneic models of colorectal cancer, the combination of trametinib and JQ1 signifi-
cantly suppressed tumour growth compared to either agent alone. Furthermore, using a 66-gene signature
we found that high expression of interferon/inflammatory genes was associated with significantly reduced
survival of colorectal cancer patients. These findings provide a novel explanation for the lack of response
to MEK inhibitors in KRAS-mutant colorectal cancer, known for its inflammatory nature. Importantly, we
have identified a novel therapeutic strategy to overcome both intrinsic and acquired resistance to MEK in-
hibition in colorectal cancer.

27. A genome-wide CRISPR screen to identify combination strategies for AZD5353 (AKTi) and

AZD8186 (PI3Kβi) in PTEN-null breast cancer

Shanade Dunn , Jason Yu , Swee Hoe Ong , Yan Zi Au , Urs Yelland , Natalie Cureton , Anna
1,4
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4
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Staniszewsla , James Pilling , Philip Hopcroft , Beverley Isherwood , Simon Barry , Barry Da-
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vies , James Lynch , Kosuke Yusa 4
1