AACR 2016
Cancer cells plasticity and drug resistance
Dr Rafaella Sordella - Cold Spring Harbor Laboratory, New York, USA
One important concept that is emerging in the last years is really this concept that resistance is not just driven by genetic mutation but there are a lot of other mechanisms that can also modify the sensitivity of cancer to therapy. In the past a lot of emphasis in this particular setting has been focussed on the tumour microenvironment and it has been shown in several different types of tumour such as leukaemia, breast cancer, colon cancer, that the tumour microenvironment basically [?? 0:36] cytokine and modification of the matrix can actually modify the sensitivity of tumours to therapy.
More recently it has also been shown that cancers are much more diverse in their composition and there is also diversity that is caused by epigenetic mechanisms. In other words, despite having the same genetic make-up they can essentially change among different cell states, that is driven by mechanisms that mostly are to epigenetic stochastic alteration. When the cells move from one state to the other they acquire a different phenotype, they completely rewire their signal transduction and so they change their dependency. In other words, if we target the EGF receptor in tumours that are driven by specific mutation in the EGF receptor, a particular subset of these cells will not be addicted to this oncogene because they will have activation of other signalling pathways that are parallel. This modification of the signalling network has really been pioneered by Neal Rosen at Sloan-Kettering in which it really has been shown that the treatment inhibition of a particular pathway can essentially activate parallel pathways. Because, again, like the signalling method within the cells it’s highly complex and during evolution of our cells they have evolved to really have a very robust signalling. So, in other words, if you block one pathway you can always find something to compensate for that.
Tell me about the cell states.
It has been shown indeed that cells, especially cancer cells, are highly plastic and they can switch among these different cell states. There’s a different cell state that has been described, some of these are really like these epigenetic driven cell states and what is interesting is that some of them acquire essentially a characteristic that they are typical of cells that they are part of tissue that are undergoing repair. This is a fascinating concept because we can also argue that maybe a tumour is a wound that never heals so there’s a subset of cells that essentially mean that this cell state that is characteristic of epithelial cells that are undergoing healing.
Another very interesting subset of cells that again represent these plastic cells are what are usually referred to as persistent cells. They have been described initially in the cell culture and some more recent data shows that maybe they can be relevant also in tumours. The difference among these different subtypes is that whilst the first one occurs naturally in the other case it’s really more like a stress response of the cells. In other words, if you treat cancer epithelial cells with a drug some of these cells go into a stress response and they change and they become more resistant to apoptosis. But this cell state, stress induced state, is really transitory so as soon as you remove the drug the cells return to a normal state. This again is very interesting because conceptually the way that we can treat then the tumour based on these different cell populations is different because in the case of the persistence you can maybe just oscillate the drug until a point in which you will generate an exhaustion of these persistent cells. In the other case instead these cells are just present in the tumour so in this case it doesn’t matter if you remove the drug, they are still there.
One interesting observation that we have made in my lab recently is that some of these cells are epigenetically driven and they are already present up front in tumours naïve to drug treatment. They actually have an intrinsic effect on repairing DNA and this is particularly interesting because it’s arguing that this particular subset of cells are highly diverse from a genetic point of view. So, in other words, you have a tumour cell that can change cell state. When you acquire and pass to this other cell state now it can accumulate more mutations, in particular copy number alteration [?? 4:44]. Therefore it generates a variety of different cells, different sisters and brothers.
This is interesting because many, many years ago, actually at Cold Spring Harbor Lab, it was described by [?? 4:57] the concept that, in this case bacterial populations, if they are more diverse they are genetically and more essentially they have a probability to become resistant to bacteriophages. So in this case it would be the same. So you increase the genetic diversity of a population so you increase the chance that there will be one particular clone that will be able to sustain drug treatment. So this is exciting.
Very evolutionary.
This is very evolutionary. So this is why biology is very interesting because you have a lot of different fields that are emerging and you can utilise knowledge acquired in a particular field and transfer it. So this is why AACR is great for this because you can just move from one room to the other and you can really be exposed to a completely different field.
What’s the next step?
The reason why I think this finding of these non-genetic mechanisms of resistance are important and they are exciting is because it’s changing also the paradigm. For example, in the case of targeted therapy in the case of lung cancer, in the lung cancer driven by mutant EGF receptor, in this case ten years ago we identified this mutation, we know that patients that have these mutations they are highly sensitive to inhibition with a particular drug that is an EGF receptor inhibitor. We know that after one year 50% of the tumours that relapse have a particular mutation that is blocking the interaction with the drug. In the four pharmaceutical companies they have developed second, third, fourth generation. So the idea is that you can continue and so progressively change.
So, if we are correct and what we are saying that now is if you have these cells they are present up front then essentially what you are doing, you are just selecting for an increased heterogeneity of cell population therefore with time you will acquire resistance much, much, much faster. So the way to do it is rather than to wait for the occurrence of this mutation is to really try to wipe out the tumour cell population as much as possible. So rather than to do a sequential treatment what we are suggesting is instead to do a combinatorial treatment, starting with. This is really resembling a paradigm developed, for example, in the case of bacteria with antibiotics or in the case of HIV in which they clearly show that a combinatorial treatment is much more effective than a single dose like sequencing.
What do you expect to see in the future?
It’s important to understand the molecular detail. So what is driving this cell plasticity? What are the mechanisms? What are these cells dependent on? In other words, to really characterise this better in the case, for example, of cell plasticity. Because in this manner then we can specifically target and we can design better combinatorial treatments to really combine these. Then of course it would be nice to start really to have clinical trials and to really try to see if this idea is correct.
