Abstract 69: Identification of new therapeutic targets and molecular predictors of response in oesophageal cancer
Authors: Chong Irene , Aronson lauren , Cunningham David , Campbell James , Ryan Colm , Davidson Michael , Chau Ian , Ashworth Alan , Lord Christopher J. 
Published: July 2016

Purpose of the study

Oesophageal cancer is the seventh most common cause of cancer related death worldwide. Disease relapse is frequent and treatment options are limited. With the exception of HER-2 and EGFR amplification, there are currently no validated biomarkers to predict response to biological therapies in this disease. The purpose of this study was to identify new biomarker defined therapeutic approaches for patients with oesophageal cancer.

Experimental approach

We have undertaken a functional screening approach focused on the druggable kinome to generate a first map of the genetic dependencies found in oesophageal cancer. A panel of 19 oesophageal and 130 non-oesophageal cancer cell lines were screened with siRNA targeting 720 kinases to generate functional profiles. By integrating this dataset with exome sequencing and copy number data, we identified key genetic dependencies (KGDs) associated with oesophageal histology (adenocarcinoma or squamous cell carcinoma) or key driver genotypes including amplifications in c-MYC, CCND1, EGFR and ERBB2, as well as loss of functional mutations in SMAD4 and ARID1A.

Results

Interrogation of the oesophageal functional genomics dataset established oncogene addiction effects including c-MYC, which is amplified in 30% of oesophageal carcinomas. We confirmed that a novel isoform of Bruton agammaglobulinaemia tyrosine kinase gene (BTK-C) was expressed in oesophageal cancer models and that silencing of BTK resulted in selective lethality in c-MYC amplified oesophageal cell lines. To further assess the impact of BTK inhibition in oesophageal cancer, we treated a panel of oesophageal cell lines with increasing doses of ibrutinib, a small molecule tyrosine kinase inhibitor of BTK. Analysis of ibrutinib SF50 revealed that there was preferential sensitivity to ibrutinib in c-MYC amplified oesophageal cell lines. Furthermore, we observed a significant association between mutation of the chromatin remodelling factor gene SMARCA4 and dependency upon the bromodomain protein BRD4. We also identified SMAD4 kinase genetic dependencies including AKT1 and a number of its substrates (FGR, MAP3K3, CHEK1 and WEE1). We noted a densely connected group of kinases that regulate the mitotic cell cycle in the SMAD4 dependency network, and found that SMAD4 mutant cell lines exhibited an increased sensitivity to drugs, including paclitaxel, that target the mitotic checkpoint.

Conclusions

Our results support the potential of BTK small molecule inhibition as a novel therapeutic strategy in c-MYC amplified oesophageal carcinoma. Loss of function SMAD4 mutations represents a candidate biomarker of response to drugs that target the mitotic checkpoint in oesophageal cancer.

Citation Format: Irene Chong, lauren Aronson, David Cunningham, James Campbell, Colm Ryan, Michael Davidson, Ian Chau, Alan Ashworth, Christopher J. Lord. Identification of new therapeutic targets and molecular predictors of response in oesophageal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 69.