Kinase Inhibitors Could Keep Cancer Patients Alive For Much Longer

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Main Category: Cancer / Oncology
Article Date: 18 Mar 2013 - 0:00 PDT


Kinase inhibitors, a class of cutting-edge cancer medications, could keep patients alive for far longer than is currently possible after scientists from the University of Sussex and The Institute of Cancer Research, England, discovered how they attack tumors.

In what they describe as an "unexpected and exciting finding"- discovering the mechanism of action of these drugs - the researchers believe they can unlock the true potential of kinase inhibitors by altering the way they are used.

Their study, which is published in current issue of Nature Chemical Biology, was sponsored by the Wellcome Trust and Cancer Research UK. Kinase inhibitors have been heralded as the new kind of targeted therapies - there are 400 of them under development and 25 already in use. As more of them become approved by regulatory authorities, the scientists say the currently 5,000 to 10,000 patients being treated with such drugs in the UK annually is set to rise dramatically.

Kinase inhibitors are effective in treating a wide range of cancers, including cancers of the lung, kidney, breast and skin. However, they can usually only extend life by approximately three to six months.

The scientists tested four kinase inhibitors and unexpectedly found that their mechanisms of action were identical; all of them are currently being used as cancer treatments:

• Erlotinib - for the treatment of non-small cell lung cancer
• Lapatinib - used for treating HER2-positive breast cancer, an aggressive disease
• Sorafenib - used for treating patients with kidney cancer, especially older patients.
• Vemurafenib - treats malignancies caused by a BRAF gene mutation which affects many patients with skin cancer

Kinase inhibitors do more than just block kinase binding to ATP

The general assumption of how kinase inhibitors work against cancer cells tells only part of the story, the researchers found. It was believed that kinase inhibitors work only because they block the cell signalling function of kinases - types of enzymes which play a very active role in many cancers - by preventing them from binding to the basic unit of energy in cells, known as ATP.

However, the scientists found that when high doses of kinase inhibitors are administered, they prevent kinases from linking up with the Hsp90-Cdc37 chaperone system, a complex of molecules in cells which play a vital role in the stability of proteins.

Professor Paul Workman FMedSci, Deputy Chief Executive of The Institute of Cancer Research (ICR), and team demonstrated that by depriving this chaperone system, the cancer-causing kinases stopped the cancer cells from growing and dividing.

Prof. Workman says the team now plans to carry out clinical trials using kinase inhibitors at high doses, but with rest periods "to take advantage of the new mechanisms". He believes this new method could keep cancer from progressing for much longer.

Prof. Workman said:

"We already knew these drugs were very effective, but we now think they could be even better. We found that several clinically used kinase inhibitors could not only disable cancer-causing kinases but also cause their destruction. It's an unexpected and exciting discovery, with major implications for how to dose these drugs to help patients live for longer.

We hope to launch a clinical trial in the next year to test the benefits of delivering kinase inhibitors in a way that should maximise their impact in destroying their targets. There is more work to do to prove the benefit to patients, but these drugs are already approved so there are fewer regulatory burdens than usual to overcome to test our new idea."

Study co-author Professor Laurence Pearl FRS, explained that their discovery could have a major impact on target cancer treatments. Kinase inhibitors are becoming important medications in modern cancer therapy.

This latest study has demonstrated another hidden power kinase inhibitors have to destroy the kinases that promote cancer growth - a power that has not yet been exploited clinically. Prof. Pearl said "It shows how important it is to understand the basic biology of how cancer drugs work. We have more work to do to understand this mechanism fully, but we are optimistic that our discovery will help many patients live for longer."


Professor Laurence Pearl

Cancer Research UK Senior Science Information Manager, Dr. Julie Sharp, said "Cancer Research UK scientists have helped to develop and test a number of kinase inhibitors. Having a better understanding of how these drugs work means that researchers can now try and fine tune their use to make them even more effective and improve survival for cancer patients."

Dr Michael Dunn, Head of Molecular and Physiological Sciences at the Wellcome Trust, said that this latest discovery has demonstrated the importance of using biology in the quest to understand how cancer medications work. He added that this "very surprising and interesting result" may well lead to more effective therapies in the future.

Written by Christian Nordqvist
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

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