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Study Finds New Reason for Drug Resistance in Kidney Cancer

In a pathbreaking development, scientists at UT Southwestern Medical Centre have found out why some types of kidney cancer stop responding to rapalogs, a class of drugs used to treat these types of cancer. With this new knowledge, patients with kidney cancer might be able to get better care.

For almost twenty years, scientists have not been able to figure out why rapalogs stop working on kidney cancer over time. An analogue is a type of drug that works against mTOR, a protein that helps cancer cells grow. People first used these medicines to treat kidney cancer in 2007.

Most of the time, cancer cells stop responding to a drug because the target protein changes, which stops it from working. But this study showed that the mTOR protein does not change in kidney cancer.

Dr. James Brugarolas' team of scientists used a novel technique to implant human kidneys and kidney tumours into mice and treat them with rapalogs until the tumours stopped responding to the drugs. The cells around the tumour, called the tumour microenvironment (TME), were able to turn on mTOR again even when the drug was still blocking it in the cancer cells. This TME has many noncancerous cells that help the tumour grow.

To demonstrate how important the TME was, scientists created mice with a form of mTOR that rapalogs could not stop. Human kidney tumours in these mice significantly reduced the effectiveness of rapalogs. This showed that the drug needs to block mTOR in both the cancer cells and the TME cells around them in order to work.

"By broadening our approach to targeting tumour support cells, we can open new avenues to fight drug resistance in kidney cancer," Dr. Brugarolas said. This means that in the future, better treatments might need to go after both the cancer cells and the TME.

The National Cancer Institute gave several grants to help pay for this study. which was published in the Proceedings of the National Academy of Sciences. The results give us new hope for making better plans to fight kidney cancer drugs that don't work as well.

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