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Cancer Drug Resist 2018;1:266-302 I http://dx.doi.org/10.20517/cdr.2018.18 Page 277

extents in the three cell lines, whereas cells migration was only stimulated in ZR-75-1. The trans-signaling
pathway significantly enhanced the growth inhibition in ZR-75-1.

Conclusion: The presence of both classic and trans-signaling occurrence in breast cancer cell lines. IL6ST
full length form is the most abundant form under basal conditions. The levels of the different IL6ST solu-
ble forms will be further studied after estrogen stimulation. The effect of IL6ST silencing in the presence of
estrogen and tamoxifen on cell growth and the gene expression is currently being examined.

22. Computational identification of drug resistance mutations to targeted cancer therapies

Teresa Kaserer, Julian Blagg

Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK

Although targeted cancer therapies have shown great success in the clinic, many patients eventually relapse
and develop resistance. The underlying mechanisms are often only dissected in clinical studies, leading to a
reactive approach towards drug resistance. We have developed a computational workflow combining drug
affinity, clonal fitness and mutational signatures to prioritize resistance mutations in the primary drug
targets, which are likely to arise upon treatment of a specific cancer type. This workflow has been validated
on a comprehensive ERK2 benchmark literature dataset and applied to successfully identify clinically-
observed resistance mutations for approved drugs targeting Kit, Abl, EGFR, and ALK. Our results suggest
that this workflow can be prospectively applied to signpost likely resistance mutations and thereby support
improved patient monitoring and the timely development of effective next-generation drugs to manage re-
sistance to targeted therapies.

23. Loss of BAP1 diminishes sensitivity to vinorelbine in Mesothelioma

Anita Singh, Dean A. Fennell, Andrew M. Fry

University of Leicester, University Road, Leicester LE1 7RH, UK

Aim: BRCA1 associated protein 1 (BAP1) is a tumor suppressor that is commonly inactivated in the major-
ity of mesotheliomas. We have previously reported that BRCA1 is lost in 38% of mesothelioma cases and
leads to vinorelbine resistance. However the mechanism of BRCA1 loss is unknown. Vinorelbine, a spindle
checkpoint activator that perturbs microtubule dynamics has shown clinical efficacy with a response rate
of 24%, whereas no other chemotherapeutic agents used in treatment of mesothelioma had a response
rate greater than 20%. The aim of the study was to explore the functional relationship between BAP1 and
BRCA1 and their role in vinorelbine resistance.

Methods: We conducted functional analysis of BAP1 and BRCA1 in MSTO (wild-type BAP1), H2452
(A95D mutation in the UCH domain), and H226 ( BAP1 null cell line) along with expression vectors carry-
ing wild-type or mutant forms of BAP1. BAP1 knockdown was achieved by siRNA transfection in MSTO
and H2452, while BRCA1 knockdown was achieved by doxycycline induction of an integrated shRNA in
MSTO.

Results: Loss of BAP1 expression led to reduced expression of BRCA1, whereas knockdown of BRCA1 did
not affect BAP1 expression. Treatment with the proteasome inhibitor, MG132, restored BRCA1 expres-
sion in the absence of BAP1 indicating that BAP1 contributes to post-translational stabilization of BRCA1
protein. Loss of BAP1 resulted in vinorelbine resistant, a phenotype similar BRCA1 deficiency. BAP1 also
promotes BRCA1 foci formation after DNA damage.