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Searching for Clues: Critical Signaling Pathways in HR+ BC

F. André (France)

SlotAA-3 Andre, F.

Fabrice André reviews three signaling pathways in HR+ breast cancer: the mTOR pathway in ER+ breast cancer, the PI3 kinase pathway in ER+ breast cancer, and the CDK4/6 pathway. The presentation considers that the mTOR pathway is a different pathway from PI3 kinase.

Transcription

Now we move to the oestrogen receptor positive, HER2 negative segment.  We have had HER2+ before with David Cameron and now we move on to oestrogen receptor positive disease.  We will have 15 minutes on some background and biology and then Javier will address more clinical questions.

Disclosures

These are my disclosures.

Full transcription

Full transcription

Now we move to the oestrogen receptor positive, HER2 negative segment.  We have had HER2+ before with David Cameron and now we move on to oestrogen receptor positive disease.  We will have 15 minutes on some background and biology and then Javier will address more clinical questions.

Disclosures

These are my disclosures.

Disclaimers

And this is general information.

Signalling pathways in HR+ breast cancer

We will review three different pathways.  The most important information in this slide is the fact that we will be talking about the mTOR pathway in ER+ breast cancer; the PI3 kinase pathway in ER+ breast cancer, and then the CDK4/6 pathway.  The important point here is that today we consider that the mTOR pathway is a different pathway from PI3 kinase, and that will be one of the goals of the presentation.

mTOR pathway: two mechanisms of activation

mTOR is a serotonin kinase that can be activated by two different pathways, and this is extremely important. 

Mechanisms of mTORC1 activation in cancer cells

The first pathway is what is called a PI3 kinase dependent pathway, while the second pathway is called the energy pathway.  This pathway goes through LKB1, AMPK and TSC1/TSC2.  This is extremely important because it means that there isn’t a perfect overlap between PI3 kinase activation and mTOR activation.

Effects of mTORC1 activation

What is the effect of mTOR activation?  The main effect of mTOR activation is to induce mRNA translation and protein synthesis: the more mTOR activation there is, the more there will be some cap-dependent translation and expression of protein synthesis.  That is the main property of mTOR, but mTOR can also have some other properties, such as phosphorylation of the oestrogen receptor, autophagy, glucose metabolism, or lipid synthesis.  However, the most important property is to generate protein synthesis: this is a kind of fuel for the cell.

Activation of AKT/mTOR pathway mediates resistance to endocrine therapy

What is the rationale to test that mTOR inhibition could reverse resistance to endocrine therapy?  This is an experiment which I like very much, which is very illustrative.  This experiment tests the efficacy of tamoxifen and, on the right hand side, you can see the efficacy of tamoxifen in a parental model, with ER+, HER2 negative.  Then, however, if you create an activation of mTOR through mutation on AKT1, then there is no longer any sensitivity to tamoxifen.  This experiment is very illustrative that, if you activate mTOR, then that induced resistance to endocrine therapy.  Of course, then the question is whether, if you  activate mTOR, that creates resistance, but then the question is whether, if you inhibit mTOR, that reverses the resistance. 

I will skip these [Referring to slides]

BOLERO-2: progression-free survival

We have this answer from clinical trials and so this is one illustration, with BOLERO-2 which is a randomised trial comparing exemestane versus exemestane plus everolimus, but there are other trials, such as the TAMRAD trial, which is a Phase II randomised trial.  There is also a Phase II trial in a neo-adjuvant setting, in combination with letrozole.  The data that supports the approval and the use of everolimus are from several randomised trial and it is not just from BOLERO-2.

BOLERO-2: predictive value of PIK3CA mutations

A very important point – and this is really the key point of the presentation – is whether mTOR activation is driven by PI3 kinase activation.  This data is very important.  This figure is reporting whether PIK3CA mutations are predictive for the efficacy of everolimus.  Here, you can see the efficacy of everolimus in patients with PIK3CA wild type, with no mutation. 

BOLERO-2: predictive value of PIK3CA mutations  

Then, when there is a mutation, the sensitivity is exactly the same.  What does it mean?  It means that PIK3CA mutations are not predictive for the efficacy of everolimus.  In terms of biology, that was extremely important because it could suggest that the activation of mTOR in ER+ HER2-negative breast cancer could actually be mediated by the energy-dependent pathway, rather than the PI3 kinase pathway.  This is important as an introduction for the next part, about the PI3 kinase pathway.

Signally pathways in HR+ Brest Cancer

The PI3 kinase pathway is frequently activated in oestrogen receptor positive breast cancer, and that leads to tumour progression and treatment resistance. 

The PI3K signalling pathway is implicated in HR+ breast cancer pathogenesis

What are the mechanisms of activation?  The most important one, and the one that is usually targeted, is the PIK3CA mutation. PIK3CA is a gene that anchors for the alpha isoform of PI3 kinase and this gene is mutated in around 25 per cent of breast cancer.

The PI3K signalling pathway is implicated in HR+ breast cancer pathogenesis

The mutation is an activated mutation: 25 per cent of breast cancers have an activating mutation of PIK3CA that leads to the activation of the alpha-isoform of PI3 kinase.

The PI3K signalling pathway is implicated in HR+ breast cancer pathogenesis

Then there are some other mechanisms of activation, with PTEN loss and activation of growth factor receptor.

The PI3K signalling pathway is implicated in HR+ breast cancer pathogenesis

 Also cross-talk with other pathways.

The PI3K signalling pathway is implicated in HR+ breast cancer pathogenesis

 Such as oestrogen receptors.

The P13K signalling pathway

Again, something that is very important in terms of dialogue between PI3 kinase and mTOR – of course, mTOR is downstream on the pathway of PI3 kinase but it is just one of several downstream pathways of PI3 kinase.  Once again, this really illustrates that PI3 kinase activation does not mean, and is not the same thing as, mTOR activation: mTOR can be activated by other pathways, and PI3 kinase can also activate other pathways than mTOR.

PI3K: four different class 1 isoforms

Now we are entering more into the structure of the kinase.  PI3 kinase in fact has four different isoforms and, as mentioned before, the most important isoform in breast cancer is the alpha isoform, which is mutated in 25 to 30 per cent of breast cancers.  The other isoforms can be important in other diseases but, in breast cancer, it is really the alpha isoform of PI3 kinase.

PI3K inhibitors: two drug families

When we go to the targeted therapies, the PI3 kinase inhibitors, there are two totally different drug families.  The first drug family, the first generation of PI3 kinase, are the pan-PI3 kinase inhibitors, and these are what we call the non-selective PI3 kinase inhibitors.  They inhibit roughly the four different isoforms.

Then there is a second generation of PI3 kinase inhibitors that are isoform-specific inhibitors.  In breast cancer, we are particularly interested in the alpha-specific inhibitor or the beta-sparing inhibitors: so there are two totally different classes of drug.

Signalling pathways in HR+ breast cancer

We now move on to the last pathway, the CDK4 pathway in ER+ breast cancer. 

The cyclin D-CDK4/6-Rb pathway is implicated in breast cancer pathogenesis

What is the CDK4 pathway?  CDK4 includes three different pathways. The first is cyclin D1 and then, downstream, there is CDK4 and then, downstream, there is Rb.  When there is activation of the pathway, that creates phosphorylation of Rb, which activates the cell cycle. 

The cyclin D-CDK4/6-Rb pathway is implicated in breast cancer pathogenesis

It is important to know that the mitogenic signalling, in the signalling pathway – like MAP kinase or PI3 kinase pathway – can then activate the cyclin D1 and CDK4 pathway.

The cyclin D-CDK4/6-Rb pathway is implicated in breast cancer pathogenesis

We know that in breast cancer there is increased activity of the cyclin D1-CDK4 pathway and that can be related to amplification of cyclin D1. 

The cyclin D-CDK4/6-Rb pathway is implicated in breast cancer pathogenesis

If there is too high a gene copy number of cyclin D1, that could create activation of the pathway.

There could be some activating mutation of CDK4/6, but that is quite rare – at least in the early phase of metastases.  There can be some loss of CDK4/6 inhibitors, such as p16 and, if the cancer loses this p16, we can create activation of the CDK4.      

The cyclin D-CDK4/6-Rb pathway is implicated in breast cancer pathogenesis

Sometimes in breast cancer,  there can be some loss of Rb, and Rb can no longer be expressed.  That creates the activation of the cell cycle. This busy slide shows that there is a strong connection between oestrogen receptor signalling and CDK4/6 pathway and that resistance to endocrine therapy can be mediated by the activation of the CDK4/6 pathway.

Signalling pathways in HR+ breast cancer

What are the perspectives? What we have seen is that, first, mTOR activation can be involved in the resistance to endocrine therapy.

Secondly, PI3 kinase pathway is frequently activated in breast cancer and the alpha-isoform of the PI3 kinase is the most important in breast cancer.

The third point is that, again, the CDK4/6 pathway is frequently activated in breast cancer through different mechanisms and it is a mechanism of resistance to endocrine therapy. 

From this point, what are the perspectives for the future?

Preclinical data support combination of PI3K and CDK4/6 inhibitors in HR+ BC

There are two different perspectives. The first is to combine the three different therapies, such as endocrine therapy plus PI3 kinase inhibitor plus CDK4 inhibitor.  This is one illustration of combinations between PI3 kinase inhibitors and a CDK4 inhibitor, where you can see that the combination between CDK4 and PI3 kinase inhibitor improves the activity of the drug.

Molecular alterations in HR+ BC are guiding optimal drug design:

alpha-selective PI3K mutation

The second important point, in terms of perspective, is about doing some molecular profiling of the breast cancer patient in order to identify the patient with PIK3CA mutation and propose to these patients a treatment with alpha-selective PI3 kinase inhibition.

Summary

This is the summary. There are three different pathways that are involved in cancer progression and resistance to endocrine therapy.  There is mTOR; there is the PI3 kinase pathway, and there is the CDK4 pathway.  These pathways can be involved in resistance to endocrine therapy but also for PI3 kinase there are some activating mutations that are oncogenic.  There are two perspectives: the first is to combine targeted therapy – the CDK4/PI3 kinase pathway - and the second perspective is to select patients based on genomic activation.