Cancer cells adapt using Darwin's 'survival of the fittest' principle to resist treatment

The research, which was jointly funded by Breakthrough Breast Cancer and Cancer Research UK, is published online in the scientific journal, Nature and gives us a better understanding of how some cancers may become resistant to treatment.

In 2004, over a quarter of a million people were diagnosed with cancer in the UK, and one in four deaths in the UK are caused by the disease**. The diagnosis and treatment of some cancers is rapidly improving, yet many tumours become resistant to treatment. This common but poorly understood problem is a key reason why treatment fails. Professor Alan Ashworth and scientists at the Breakthrough Breast Cancer Research Centre at The Institute of Cancer Research have gained a unique insight into how resistance to certain drugs occurs by identifying a genetic mechanism that can reverse cancer cells' sensitivity to specific types of treatment, making them become resistant.

Poorly understood

Professor Ashworth, Director of the Breakthrough Breast Cancer Research Centre, said; "Drug resistance is a problem common to all types of cancer, yet this important process is poorly understood. Our work has shown how this occurs in some women with cancer and in the future, we hope to be able to use this information to predict whether cancer patients will benefit from particular treatments. Furthermore, this information will help us to develop ways of countering the problem of resistance."

The research was based on studying tumour cells containing a faulty version of the breast cancer gene, BRCA2. Women who inherit this faulty gene are at a much higher risk of developing breast and ovarian cancer. Professor Ashworth's group demonstrated in 2005 that the cancers these women develop are extremely sensitive to drugs such as PARP inhibitors and the platinum-based chemotherapy drug, carboplatin, that target a weakness in cancer cells arising from this faulty gene. This means that, unlike cells with normal BRCA2 genes, they are unable to repair damaged DNA properly. These therapies are currently being tested in clinical trials for breast and ovarian cancer.

Faulty cells

To uncover how cancer cells become resistant to treatment by PARP inhibitors or carboplatin, scientists took tumour cells that contained faulty BRCA2 genes and then made them resistant to both of these treatments. They also studied tumour cells from women with a faulty BRCA2 gene, whose ovarian cancers had become resistant to carboplatin. In both instances, they uncovered a previously unknown genetic mechanism that had altered the faulty BRCA2 gene in the cancer cells, restoring its normal functions and making the cancer resistant to treatment.

This new version of BRCA2 restored the ability of cancer cells to repair genetic damage caused by the anti-cancer drugs, allowing them to survive. Scientists at the Breakthrough Breast Cancer Research Centre believe this particular mechanism of resistance might be a common way by which many other types of cancer become resistant to treatment.

Professor Alan Ashworth adds; "This genetic mechanism works like Charles Darwin's natural selection theory - it allows cancer cells to survive by changing the way treatments affect them. By understanding this process we can alter patient treatment to counter the problem of resistance."

Increasingly important

Professor Herbie Newell, Cancer Research UK's executive director of translational research, said: "This research deepens our understanding of why some breast cancer patients with a faulty BRCA2 gene may stop responding to treatment. This type of research is becoming increasingly important as we seek to tailor cancer therapies to individual patients. Although at an early stage, this research may ensure that women are spared unnecessary treatment."

This research is just one example of the groundbreaking work taking place at the Breakthrough Breast Cancer Research Centre at The Institute of Cancer Research, Europe's leading cancer research centre. One area of the centre's work is to identify genetic changes that take place in breast cancer cells and use this knowledge to benefit patients in the clinic.

Breakthrough Breast Cancer needs to raise at least £25 million each year for the next three years to support its vital research, campaigning and education work. For more information about Breakthrough Breast Cancer, please visit http://www.breakthrough.org.uk.

* Resistance to PARP Inhibition Caused by Intragenic Deletion in BRCA2 by Stacey L. Edwards, Rachel Brough, Christopher J. Lord, Rachael Natrajan, Radost Vatcheva, Douglas A. Levine, Jeff Boyd, Jorge S. Reis-Filho and Alan Ashworth.

** CancerStats, CRUK http://info.cancerresearchuk.org/cancerstats/?a=5441

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