Understanding the mechanisms of breast cancer resistance

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Published: 18 Jul 2012
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Prof Jos Jonkers – Netherlands Cancer Institute, Amsterdam, Netherlands

Prof Jos Jonkers talks to ecancer.tv about the use of mouse models to understand the mechanisms underlying breast cancer resistance.

Research into BRCA positive breast cancer in mice has shown that resistance can result from the reactivation of the BRCA mutation, however there are likely to be many ways that resistance can develop.

Prof Jonkers explains how this research could translate into clinical benefits to both BRCA mutated breast cancer and other types of tumour.

The European Association for Cancer Research, 7-10 July 2012, Barcelona, Spain

 

Understanding the mechanisms of breast cancer resistance

 

Professor Jos Jonkers – Netherlands Cancer Institute, Amsterdam, Netherlands

 

 

Today I talked about how we use our mouse models of human breast cancer to understand the therapy response and resistance. Basically, it revolves all around hereditary breast cancer, BRCA1 associated breast cancer, which is supposed to be quite sensitive to certain chemotherapeutics like platinum drugs but also to novel, more toxic, inhibitors called PARP inhibitors. So we set out to test these therapies, these therapeutic agents, in our mice in order to understand if we can now eradicate the disease, which we didn’t, which is, of course, also clinically relevant. In the absence of eradication we sought to understand the mechanisms underlying the lack of eradication and the induction of resistance that kicked in.

 

What was your understanding of why people become resistant?

 

What we learned was that the idea that was coined in the late 2000s, namely that these drugs would really be perfect human drug combinations where cells could only escape by reverting to primary defect, that is inactivation of BRCA1 by restoring the defect, that this doesn’t seem to be the complete picture. So it’s clear then that there are many more ways to acquire resistance than to refer to primary defect.

 

Where do we go next with this?

 

I think that the important point is that what we do with all this work in the pre-clinical models is to come up with a list of candidate mechanisms that may also catalyse resistance in the clinic. Now I think that the companies that are doctors as well have a better tool to, on the one hand, use a prompt as candidate biomarkers to determine whether a tumour would be sensitive or not, but also if tumours acquire resistance to then test these candidate mechanisms that we have identified.

 

Why is the hereditary aspect important?

 

The hereditary aspect is important because actually how this is how that specific field started. Inactivation of BRCA1 leads to loss of double strand break repair via homologous recombination, this is an error free repair pathway. These drugs that we’ve been using all put extra stress on that pathway to the extent that normal cells can still cope with that extra stress but BRCA1 deficient tumour cells cannot. In addition to the hereditary cancers, we also know that there are more tumours, also sporadic tumours, that have a BRCA1-like phenotype and this is where we’ve been using so-called patients derived xenograft models to study responses and resistance of these tumours. And in fact we find that also these tumours respond quite well, of course all in the face of ultimate acquired resistance, but they also respond quite well to these inhibitors thus expanding the target population from only hereditary breast cancer patients to also sporadic cancer patients with a BRCA1-like phenotype.