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Genetic and transcriptional evolution alters cancer cell line drug response

In this paper, published in Nature, the authors analysed how different cancer cells are – not so much from the original tumor samples but from other batches of what are supposed to be the exact same cells. Cancer cell lines tend to be genomically unstable in general and in this article, the authors provide interesting numbers to quantify this issue. The team looked at 106 tumor cells lines and found that there is a very large amount of heterogeneity when examined closely (by deep sequencing, RNA-sequencing, cell painting assay, etc.). The results show that established cancer cell lines, generally thought to be clonal, are in fact highly genetically heterogeneous. This heterogeneity results from both, clonal dynamics (i.e. changes in the abundance of pre-existing subclones) and from continuous instability (i.e. the appearance of new genetic variants). Moreover, genetic heterogeneity can lead to varying patterns of gene expression, which in turn result in differential drug sensitivity.
For example, the authors took 27 different samples of “MCF7” cells (a widely used breast cancer derived line) and tested 321 known oncology compounds across them. At least 75% of the compounds that showed strong growth inhibition of one MCF7 line were totally inactive against others.
It can easily be imagined how this finding can influence the reproducibility of cancer research studies and this paper is a loud warning for scientists to tackle this problem. On the other side, this heterogeneity can be an opportunity to learn more about cancer cell biology – but only if scientists are aware that it exists!
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