Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib.

New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and the poor response to standard chemotherapy. Using a series of high-throughput cell-based drug screens in OCCC tumor cell models, we have identified a synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and a key driver in OCCC, ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo, suggesting that this is a robust synthetic lethal interaction. The sensitivity of ARID1A-deficient cells to dasatinib was associated with G1-S cell-cycle arrest and was dependent upon both p21 and Rb. Using focused siRNA screens and kinase profiling, we showed that ARID1A-mutant OCCC tumor cells are addicted to the dasatinib target YES1. This suggests that dasatinib merits investigation for the treatment of patients with ARID1A-mutant OCCC. Mol Cancer Ther; 15(7); 1472-84. ©2016 AACR.

Molecular characterisation of cell line models for triple-negative breast cancers.

BACKGROUND: Triple-negative breast cancers (BC) represent a heterogeneous subtype of BCs, generally associated with an aggressive clinical course and where targeted therapies are currently limited. Target validation studies for all BC subtypes have largely employed established BC cell lines, which have proven to be effective tools for drug discovery. RESULTS: Given the lines of evidence suggesting that BC cell lines are effective tools for drug discovery, we assessed the similarities between triple-negative BCs and cell lines, to identify in vitro representatives, modelling the diversity within this BC subtype. 25 BC cell lines, enriched for those lacking ER, PR and HER2 expression, were subjected to transcriptomic, genomic and epigenomic profiling analyses and comparisons were made to existing knowledge of corresponding perturbations in triple-negative BCs. Transcriptional analysis segregated ER-negative BC cell lines into three groups, displaying distinctive abundances for genes involved in epithelial-mesenchymal transition, apocrine and high-grade carcinomas. DNA copy number aberrations of triple-negative BCs were well represented in cell lines and genes with coordinately altered gene expression showed similar patterns in tumours and cell lines. Methylation events in triple-negative BCs were mostly retained in epigenomes of cell lines. Combined methylation and gene expression analyses revealed a subset of genes characteristic of the Claudin-low BC subtype, exhibiting epigenetic-regulated gene expression in BC cell lines and tumours, suggesting that methylation patterns are likely to underpin subtype-specificity. CONCLUSION: Here, we provide a comprehensive analysis of triple-negative BC features on several molecular levels in BC cell lines, thereby creating an in-depth resource to access the suitability of individual lines as experimental models for studying BC tumour biology, biomarkers and possible therapeutic targets in the context of preclinical target validation.

Influence of whole arm loss of chromosome 16q on gene expression patterns in oestrogen receptor-positive, invasive breast cancer.

A whole chromosome arm loss of 16q belongs to the most frequent and earliest chromosomal alterations in invasive and in situ breast cancers of all common subtypes. Besides E-cadherin, several putative tumour suppressor genes residing on 16q in breast cancer have been investigated. However, the significance of these findings has remained unclear. Thus, other mechanisms leading to gene loss of function (eg haploinsufficiency, or distortion of multiple regulative subnetworks) remain to be tested as a hypothesis. To define the effect on gene expression of whole-arm loss of chromosome 16q in invasive breast cancer, we performed global gene expression analysis on a series of 18 genetically extensively characterized invasive ductal breast carcinomas and verified the results by quantitative real-time PCR (qRT-PCR). The distribution of the differential genes across the genome and their expression status was studied. A second approach by qRT-PCR in an independent series of 30 breast carcinomas helped to narrow down the observed effect. Whole-arm chromosome 16q losses, irrespective of other chromosomal changes, are associated with decreased expression of a number of candidate genes located on 16q (eg CDA08, CGI-128, SNTB2, NQO1, SF3B3, KIAA0174, ATBF1, GABARAPL2, KARS, GCSH, MBTPS1 and ZDHHC7) in breast carcinomas with a low degree of genetic instability. qRT-PCR provided evidence to suggest that the expression of these genes was reduced in a gene dosage-dependent manner. The differential expression of the candidate genes according to the chromosomal 16q-status vanished in genetically advanced breast cancer cases and changed ER status. These results corroborate previous reports about the importance of whole-arm loss of chromosome 16q in breast carcinogenesis and give evidence for the first time that haploinsufficiency, in the sense of a gene dosage effect, might be an important contributing factor in the early steps of breast carcinogenesis.