The SUM-185PE cell line was a mystery to our lab for quite some time, and because of that, it was several years after the establishment of the cell line before we did much work with it. Interestingly, it was the genomic analysis of this line that shed light on it’s underlying biology and provided important clues regarding a therapeutic strategy that is highly effective against these cells, and other similar breast cancer cells. After examining these cells for the most common amplified oncogenes in breast cancer, and finding none, we performed a genome-scale gene amplification experiment using Agilent comparative genomic hybridization (CGH) arrays, and we coupled that with gene expression profiling performed on Illumina bead arrays. From this analysis, we identified an area of focal gene amplification in the 4p16 chromosomal region, and identified FGFR3 as a gene that was highly overexpressed from this region. Further study showed that SUM-185PE cells were highly sensitive to the FGFR inhibitor PD173074, and we ultimately found that FGFR3 was a strong hit in our genome-scale shRNA screen. Thus, it became clear that FGFR3 is a driving oncogene in SUM-185PE cells. Further genomic analysis of this cell line showed that, in addition to FGFR3, the anti-apoptosis gene BCL2L1 is also amplified and overexpressed in these cells, and also a hit in the functional screen. Finally, exome sequencing of the cell line revealed the presence of the common p.H1047R point mutation in the PIK3CA gene. Thus, the oncogene signature of the SUM-185 cells contains three druggable oncogenes, and we have demonstrated that attacking these genes with combinations of targeted drugs has a profound effect on the survival of these cells as well as other breast cancer cells with similar oncogene signatures. Indeed, treatment of SUM-185PE cells with a single administration of low concentrations of the FGFR inhibitor PD173074 in combination with Navitoclax, which targets BCL2L1, and A66 which specifically targets the product of the PIK3CA gene results in a greater than 1000-fold reduction in the clonogenic potential of the cells. Indeed, visual inspection of the cells shows that the vast majority of the cells undergo apoptosis within 48 hours of treatment. By contrast, this drug regimen has no effect on the clonogenic potential of MCF-10A cells, or other breast cancer cells that do not exhibit this oncogene signature. Thus, functional genomic analysis of the SUM-185PE cell line resulted in the identification of a potent targeted drug strategy that could be effective in other cancer cells that exhibit activation of a druggable receptor tyrosine kinase oncogene along with amplification and overexpression of BCL2L1. (See PMID 27153554 )
The fact that SUM-185 cells have activated oncogenes that drive classical cell signaling pathways is reflected in the analysis of the genome-scale shRNA screen results which indicate a large number of essential genes that map to the PI3’K/AKT pathway, the Apoptosis pathway, and the FoxO signaling pathway.
In addition to our work on the SUM-185PE cells, other labs have performed expression profiling of these cells and have classified them as being part of a cluster of cancer cells that express the androgen receptor and exhibit the expression profile of androgen receptor subclass of triple negative breast cancers. Thus, this signature presents yet another opportunity for a targeted drug approach for these cells and other similar breast cancer cells.
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