Professor Spiros Linardopoulos and his team at our research centre have discovered that genetic mutations promoting resistance to a particular type of cancer treatment can be present in breast cells before breast cancer has developed.
Wednesday 22 July 2015      Research blog
Naturally selected resistance to cancer drugs

The day Charles Darwin stepped off the Beagle upon the shores of the Galapagos Islands in 1835 would turn out to be one of the most important days in human history. Under the equatorial sun of these Pacific Islands, Darwin noted that finches appeared similar across all the islands, yet carried physical characteristics suited to the varying qualities of the islands themselves. This observation, and countless others made by Darwin on the Beagle voyage, led to one of the greatest scientific texts of all time – On the Origin of Species by Means of Natural Selection.

In this book, Darwin explains how variation between species could emerge by the selective pressure exerted by the environment. His central dogma was that this pressure pushes populations to evolve over the course of generations and is responsible for the immense diversity of life on our planet. One of the most famous images associated with On the Origin of Species is the “tree of life” diagram taken from one of Darwin’s notebooks. It elegantly displays how natural selection can create a branched tree over time as one species evolves with an eclectic mix of adaptions.

Branches of a tree

It turns out that this branched evolution is echoed at a cellular level – in particular the evolution of cancer in a single person. Years of scrutinising cancer genomes has finally led to an understanding that the tree of life also drives an astonishing amount of diversity in cancer cells from a single tumour. This diversity is called “intratumour heterogeneity” and goes a long way to explaining the complexity of the disease.

It turns out that Darwin’s branched evolution may also be responsible for the development of resistance to cancer treatments so often seen in the clinic. It’s one of the biggest issues with cancer drugs today and even wonder drugs like tamoxifen aren’t exempt – the drug doesn’t always stop hormone-positive breast cancer in its tracks. There are several theories still under investigation about how drug resistance emerges and a lot of research is being done to find out how it can be prevented, or at least circumvented.

Pre-existing or forced?

One way that resistance could emerge is through the high rate at which cancer cells replicate and the pressure this puts on the stability of their genomes. Cancer cells are genetically unstable due to the fact they are dividing uncontrollably, allowing them to rapidly pick up many more mutations than you would expect in a normal cell. Introducing an anti-cancer drug to these cells may cause mutations that then provide the cells with a better chance of survival – driving an evolutionary change in the cells akin to the adaptation of Darwin’s finches to the individual island environments.

There’s another idea, that mutations allowing resistance are pre-existing and that treatment acts as a selective pressure, eradicating non-resistant cancer cells and leaving behind ones that continue to survive and multiply, resulting in a tumour highly populated with resistant cancer cells. From a clinical perspective, this idea is really interesting because it may allow us to detect cancers with the ability to develop resistance later on, before treatment has even started, giving doctors the opportunity to deliver a cocktail of drugs to stop it from ever becoming a problem.

Inherent resistance

Dr Spiros Linardopolous

New research from Breast Cancer Now scientist Professor Spiros Linardopoulos and his team at Breast Cancer Now’s research centre has now shown unequivocally that resistance to some drugs can be detected in healthy breast tissue before cancer has even developed. The team set out to discover what makes cancer cells resistant to MPS1 inhibitors, a new type of cancer drug currently in development, and discovered five separate mutations to the MPS1 gene that confer resistance.

Interestingly, these five mutations were found to be present at a low frequency in primary breast tumours, and breast cells from healthy donors, both of which had never been exposed to a MPS1 inhibitor. This would back up the notion that these resistant mutations are pre-existing and not solely driven by the high mutation rate of cancer cells.

Although found at a low frequency, these mutations can be rapidly amplified in a population of cells once a selective pressure is introduced, such as a MPS1 inhibitor. Professor Linardopoulos and his team showed how this could work in the lab by first showing that many cancer cell lines used routinely in research also contain a low frequency of resistance mutations to the MPS1 gene. They then treated a population of these cells with a MPS1 inhibitor and showed that while a majority of the cells were initially killed, the ones with the resistant mutations persisted and rapidly multiplied, filling the space that was available with drug resistant cells.

An even more significant finding from this work was that a common genetic mutation that causes resistance to the Epidermal Growth Factor Receptor (EGFR) inhibitor, gefitinib, is also present in healthy breast tissue cells. This suggests that this mechanism of resistance may be crucial for understanding resistance to other cancer drugs.

From lab to clinic

Drug development is an expensive and time consuming process with no guarantee of success.  Resistance to new cancer drugs is almost inevitable so identifying resistant mutations early on in the drug discovery pipeline (as done here with MPS1 inhibitors) allows scientists to design and synthesise new drugs that target the resistance and keep ahead of the cancer. Professor Linardopoulos has already begun to work on this through his connections with the Cancer Research UK Cancer Therapeutics Unit at the Institute of Cancer Research.

If we know what causes resistance to a drug before it progresses through clinical trials, it could be possible to design trials around a cocktail of drugs aimed at circumventing resistance before it emerges, ultimately speeding up the drug discovery process.

Baboons to bacteria

As Darwin left the shores of the Galapagos, sketches and notes in hand, he may have already realised how significant the next step of his journey would be. But it’s doubtful he could have envisaged the far-reaching impact of his theory of evolution by natural selection. From baboons to bacteria and to the cells of a life-threatening tumour, natural selection charts a chaotic course that ultimately pushes the best adapted into the spotlight. Understanding how this drives the evolution of cancers – in particular the emergence of drug resistance – is going to be key to ensure that the drugs we design outsmart breast cancer, and give patients the best possible chances of overcoming the disease.

Dr Matthew Lam

More on this story

Resistance to cancer drug found to occur naturally in the breast