Complexity of intra- and inter-pathway loops in colon cancer and melanoma: Implications for targeted therapies

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Published: 26 Jun 2014
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Prof René Bernards - Netherlands Cancer Institute, Amsterdam, The Netherlands

Prof Bernards talks to ecancertv at WIN 2014 about the complexity of intra- and inter-pathway loops in colon cancer and melanoma and the implications for targeted therapies.

I discussed this morning how do we use genetic tools to identify the best possible combination therapies for individual cancers. We of course know that we can select patients for therapy based on mutations in the genome but we also know now that single agent targeted therapies are often only transiently effective and resistance rapidly arises. So we need to think of combinations and the question then is which of the many possible combinations of targeted agents are the best for any given patient. You can either test that empirically by just trying combinations that seem to make sense based on your knowledge of the pathways that are driving cancer in a given cancer case; that has shown some benefit for patients but I use what we call an unbiased approach where we simply ask if we inactivate all the kinases that are potentially contributing to signalling one by one, which kinase when inhibited is showing the strongest synergy with a given anti-cancer drug for our patient? That gives us the strongest combination of two kinases to inhibit in cancer that are synergising to kill the cancer cell. We have shown some really promising results of that, not only in the pre-clinic where we showed that BRAF inhibition in colon cancer really requires co-inhibition of EGFR and now recently we have seen the first clinical results of that concept that BRAF plus EGFR inhibition is indeed very effective in early stage clinical trials in BRAF in colon cancer. So taking it from a proof of concept in the laboratory to clinical evidence in the clinic in about one year’s time is a very short time frame to bring anything to the clinic. This will only become quicker in the future because we are now at a stage in our knowledge of cancer that we can really quickly translate new insights into novel clinical concepts and test those experimentally in the clinic. So I would say comprehensive cancer centres where research and treatment are under one roof, where you can really have a dialogue between clinicians and basic scientists, is becoming more and more important as our insights in what are the driver mutations in cancer grow and how we translate that knowledge into better therapies.

What are intra- and inter-pathway loops mentioned in the title of your talk?

Our cells are geared to be very resilient and resilience means that you can deal with perturbations of the normal homeostasis in the cell. To be able to survive under very adverse conditions our cells have, during evolution, built up a number of feedback loops and cross-talk loops where if you inhibit one pathway another pathway gets reactivated so that the cell can deal with the perturbation of the pathway. That is good for cells to survive under harsh conditions but it’s bad if you want to kill a cancer cell because if you inhibit one pathway it leads automatically to activation of a secondary pathway that then precludes the inhibition of that first pathway to be effective, then you accomplish very little with inhibition of that pathway. So we need to learn which those loops are and the cross-talks between pathways to now find the effective combinations that we not only inhibit the primary pathway but also the feedback system that is reactivated when we inhibit the primary pathway. That is what I think our genetic screens are good at finding. They tell us if you inhibit this pathway the reason that that inhibition is not very effective is because there is a secondary pathway being activated and that’s why you see only limited efficacy of that pathway.

There is no reason to look at colon cancer or melanoma in particular, I think these principles apply to all cancers and we are, in fact, studying in my lab now also lung cancer, breast cancer, pancreatic cancer for feedback systems. So these systems apply, these feedback loops are present in all cell systems and there is no reason that they would be selective for colon or melanoma, it’s just where we started and got some initial successes and now we’re expanding into other cancer types.

The overall take home message is that combination therapies are the answer to drug resistance, the problem is that there are so many possible combinations that we cannot test them all and that we need good tools to select the most promising combinations. You find the most promising combinations not by thinking you are smart and that you know how to combine drugs but the best way is to have an unbiased approach where you let the biology of the cancer speak to you and ask if I simply at random inactivate all the kinases one by one which one shows the strongest synergy. Often you find a gene that you least expected to be synergistic so it tells you that your knowledge of the pathways is really not sufficient to make appropriate predictions as to what are the strongest combinations. So if you think you’re smart the take home message is you’re not, biology is often far more complicated than we think and our knowledge is too limited to make educated guesses. Therefore an unbiased approach is at this point still the best way forward to find combinations.