Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
and pS6 in a responder model and no change in phosphorylated proteins in
non-responding models were observed. Pharmacodynamics studies, validation
of responders with more mouse replicates, and testing on the remaining models
are ongoing and the results will be reported. Conclusion: 60% of LUSC PDXs
with PIK3CA mutation demonstrate high sensitivity to pan-PI3K inhibitor.
Understanding innate resistance mechanisms of PI3K inhibition may provide
important insights on tractable targets and therapeutic strategy for LUSC
patients with aberrant PI3K pathway.
Keywords: patient-derived xenografts, Lung Squamous cell carcinoma,
BKM120, PI3K
POSTER SESSION 2 – P2.03B: ADVANCED NSCLC & CHEMOTHERAPY/TARGETED THERAPY/
IMMUNOTHERAPY
BIOMARKERS –
TUESDAY, DECEMBER 6, 2016
P2.03B-072 RESISTANCE TO BET INHIBITORS IN LUNG
ADENOCARCINOMA IS MEDIATED THROUGH A MYC INDEPENDENT
MECHANISM
Jack Calder 1 , Amy Nagelberg 2 , Will Lockwood 2
1 Integrative Oncology, BC Cancer Research Center, Vancouver/Canada, 2 BC Cancer
Research Center, Vancouver/BC/Canada
Background: JQ1 is an inhibitor of the bromodomain and extraterminal (BET)
family proteins, which function as important reader molecules of acetylated
histones and recruit transcriptional activators to specific promoter sites.
BET proteins have been shown to control the expression of numerous
genes involved in cell cycle, cell growth, and cancer. The down-regulation of
c-MYChas been linked to JQ1 inhibition in many non-lung cancer cell lines, while
reactivation of c-MYC expression, through co-regulation by GLI2 or activation
of Wnt signaling, has been shown to induce JQ1 resistance. However, our lab
has previously shown that lung adenocarcima (LAC) cells are inhibited by JQ1
through a mechanism independent of c-MYC down-regulation,identifying
FOSL1 as a possible target in LAC cells. This suggests that the epigenetic
landscape of cells from different origins and differentiation states influences
response to JQ1. This study aims to identify potential mechanisms regulating
resistance to JQ1 in LAC in order to determine if the epigenome affects this
process in different cancer types. Methods: LAC cell lines sensitive to JQ1
treatment, H23 and H1975, were passaged with increasing concentrations
of JQ1 until the cells were resistant to high doses of the drug. Expression
profiles were generated for parental and resistant cells using Affymetrix
Human PrimeView Arrays and genes differentially expressed between the
states for each cell line were identified and compared across both H23 and
H1975 to identify candidate genes. Protein expression was evaluated through
Western Blot analysis to confirm gene changes associated with resistance.
Results: Initial morphological and western blot analysis showed resistant
H1975 cells underwent EMT transition with significant decrease in E-cadherin
and increase in Vimentin. Analysis of differentially expressed genes between
the parental and resistant pairs identified 101 significantly differentially
expressed genes (Benjamini-Hochberg corrected p-value