Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine . All content is Derek’s own, and he does not in any way speak for his employer.

There are a lot of cancer cell lines out there, and many of them get used a lot, too. It’s not surprising, in a way, because these are cells that have already (and unfortunately) proven themselves to be robust and fast-growing, so many of these lines tend to take to cell culture conditions pretty well. In the case of HeLa cells, too well – over the years, there have been more cases than you’d like to think about where HeLas have contaminated other cell lines and crowded them out without the the researchers involved noticing for a while. That doesn’t happen as often as it used to (cheaper sequencing and people in general being more aware of the problem), but it’s always out there.

As you’d imagine, these cells lines are very important in oncology drug development, being located way up near the top of the screening cascade. They’re used both to see if you’re affecting the sorts of tumors you hope to target, and to get some idea of selectivity across different types. Now, everyone knows that these lines don’t really reflect what’s going on in an actual tumor – it’s a different environment in general, and after cells have been in culture a while they tend to be different beasts than they were at the start – but it’s still a lot better than running no cell assay at all.

Here’s a new paper, though, that goes into detail about just how different those cells are, and not so much from the original tumor samples, as from other batches of what are supposed to be the exact same cells. That’s not so good. Cancer cell lines tend to be genomically unstable in general, which is a problem, but here are the numbers for just how much of a problem that is. This team looked at 106 tumor cells lines and found that there’s a very large amount of heterogeneity in them when examined closely (deep sequencing, RNA-seq, cell painting assay, and more).

Our results show that established cancer cell lines, generally thought to be clonal, are in fact highly genetically heterogeneous. This heterogeneity results both from clonal dynamics (that is, changes in the abundance of pre-existing subclones) and from continuous instability (that is, the appearance of new genetic variants). Moreover, genetic heterogeneity leads to varying patterns of gene expression, which in turn result in differential drug sensitivity. These findings have a number of important implications. . .

For example, they took 27 different samples of what are all labeled “MCF7” cells (a widely used breast cancer derived line) and compared 321 known oncology compounds across them. At least 75% of the compounds that showed strong inhibition of one MCF7 line were totally inactive against others. That’s going to confound experiments big-time, and this paper is a loud warning for people to be aware of this problem and to do something about it. On the flip side, this heterogeneity can be an opportunity to learn more about cancer cell biology and compound effects on it – but only if you’re aware that it exists!