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Double-pronged attack overcomes bladder cancer’s drug resistance

Researchers at The Institute of Cancer Research, London, found that using two types of drug known as FGFR inhibitors and EGFR inhibitors together had a more dramatic and longer-lasting effect on tumours in mice than single drug therapy.

The research was funded by Cancer Research UK and is published in the journal Cancer Discovery.

Around 40% of bladder cancers are caused by genetic mutations which over-activate a protein called FGFR3, causing cells to divide uncontrollably. However, treatment is not as simple as just blocking FGFR3.

“Resistance is a major problem,” said study leader Dr Nicholas Turner, head of the molecular oncology team at the Institute of Cancer Research (ICR) and Honorary Consultant in Medical Oncology at The Royal Marsden. “It is difficult to know how tumours will respond to FGFR inhibitors and what causes resistance.”

In the new study, Dr Turner’s team found that resistance to FGFR inhibitors was strongly related to the action of EGFR. EGFR is another protein involved in cell division, and is implicated in the growth of many cancers. The team found that when they blocked FGFR, the activity of EGFR increased to compensate.

The study showed that combining FGFR and EGFR inhibitors significantly increased the overall effectiveness of treatments. Whereas FGFR inhibitors alone did stop tumour growth, they continued to grow rapidly once treatment was stopped. By contrast, combining FGFR and EGFR inhibitors actually caused tumours to shrink and remain reduced after treatment.

Dr Turner said: “We found that combining FGFR and EGFR inhibitors led to sustained tumour reduction, making it a promising treatment strategy. Although other resistances may develop after we block EGFR, we can start by addressing this main resistance and tackle any other issues as they arise.”

Understanding the relationship between FGFR and EGFR could ultimately lead to improved treatments for bladder cancer as well as other cancers with mutated FGFR genes.

Dr Robert Huddart, Reader in Urological Oncology at the ICR and Consultant Clinical Oncologist at The Royal Marsden, said: “New therapies for bladder cancer are urgently needed, with no major advances in drug treatment for more than 10 years Both FGFR and EGFR mutations seem to be important mutations in bladder cancer development and studies of agents against both mutations are underway in the UK and beyond. This work suggests that a new approach attacking both abnormalities may be more effective and better for patients than attacking each individually. This holds hope for better treatment approaches for bladder cancer patients.”

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