Drug resistance mechanisms

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Published: 22 Dec 2015
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Dr Floris Groenendijk - Erasmus Medical Center, Rotterdam, Netherlands

Dr Groenendijk goes through the main points of his talk the 3rd EurocanPlatform Translational Research Course, on resistance to targeted therapies in cancer. He emphasises the need for combination therapies over sequential therapies to maximise treatment effectiveness.

He explores the clinical significance this research could have, especially in terms of increasing overall survival in patients receiving targeted therapies. He gives examples of drug resistance, such as with vemurafenib in melanoma.

He then goes through the next steps this field will take, what obstacles they face and what the eventual benefit will be.


3rd EurocanPlatform Translational Research Course

Drug resistance mechanisms

Dr Floris Groenendijk - Erasmus Medical Center, Rotterdam, Netherlands

My talk is about mechanisms of resistance to targeted therapies and the main message of my talk is that the resistance to targeted therapies is often caused by reactivation of the signalling pathway that is inhibited by the cancer drug or by secondary alterations of the drug target, that’s the main thing. Then the second main message of my talk is that sequential therapies of targeted therapies is often a perfect recipe for certain treatment failure and that we have to think about combination therapies instead of sequential therapies.

What significance does this have for clinical practice?

We have all seen the dramatic responses that patients often have to these targeted therapies but the problem is that those responses are often not durable. So patients will have an increase in their progression free survival but their overall survival is not significantly changed by the targeted therapies. So we have to think about why is this happening and that is usually because the cancer cells become resistant to the targeted therapies. So if we want to overcome this resistance we have to think about new strategies, like combination therapies, or improving our compounds to overcome this drug resistance and that will hopefully increase the survival for cancer patients as well.

Can you give any examples?

I will show several examples of the literature of basically the last fifteen years. For example, what I will show is that cancer cells often reactivate the pathway by upstream or downstream alterations in the same signalling pathway. I think a striking example is the treatment of melanoma with vemurafenib for BRAF V600E mutated melanoma patients. What we have seen is that those cells often become resistant due to upregulation of the drug-targeted cells like the BRAF so they amplify the BRAF gene, or by upstream alterations like the KRAS mutations or by alterations in the EGFR gene, more upstream, or even downstream like MEK mutations. So it’s all in the same signalling pathway that cells become resistant to the targeted therapy.

What are the next steps?

What I think is really booming now is that we’ve started looking at not only the cancer, the tumour itself, but only to look in the blood of the cancer patients. So we can already see before the cancer cells actually start growing out, we can already see which alterations are likely, the prospects of the drug resistance. So I think that is one aspect that will definitely increase in the coming years. I also think we are better in making our compounds so we can make smarter compounds that can already better cope with these cancer cells.

Besides money, what obstacles have you faced?

The cancers are smarter than we think that we are so far. So usually the cancer cells can find a way to circumvent the inhibition of the pathway so they can reactivate an alternative parallel signalling pathway and we have to think more about rational combination treatments and not only focus on the pathway that is inhibited or that is altered by the cancer cells.

What will be the eventual benefit of this work?

I think always this work will help us in identifying new resistance mechanisms and also identifying new strategies to overcome and ultimately also really overcome drug resistance, not only delay the emerging of drug resistance.

Do you have a take home message?

The main take home message from my talk is that sequential treatment with targeted therapies is basically useless because cancer cells can always find a way to become resistant to single agent therapy. So we have to think up front about strong combination therapies and about combination therapies that are driven by basically biology.