20 March 2013

The antitumor potential of kinase inhibitors was underestimated

Drugs of the kinase inhibitor class are among the most well-known representatives of a new type of directed pharmacological agents. 25 of them have already found their application in clinical practice and about 400 more are at different stages of development. Kinase inhibitors are used to treat malignant tumors of various localization, including breast, skin, lungs and kidneys, but in many cases they prolong the life of patients by only 3-6 months.

Scientists of the Institute of Cancer Research, part of the University of Sussex, believe that they have found a way to more fully unlock the potential of these drugs by changing the method of their use.

Previously, it was believed that the mechanism of action of kinase inhibitors consists solely in blocking the signaling function of kinase–class enzymes that play an important role in the development of many types of cancerous tumors by preventing their binding to ATP molecules - the main energy carriers of the cell.

The researchers found that this is not all that drugs of this class are capable of. In high doses, they prevent the binding of kinases to a complex of molecules known as the Hsp90-Cdc37 chaperone system, which plays an important role in maintaining the stability of proteins. Experiments have shown that such "chaperone deprivation" literally destroys the molecules of kinases that ensure malignancy and stops the growth and division of cancer cells.

The authors are very inspired by the fact that this hidden mechanism is similarly manifested in the use of all four tested kinase inhibitors currently used in clinical practice, namely:

  • vemurafenib, used to treat tumors caused by a mutation of the BRAF gene, including melanoma;
  • lapatinib, used in the treatment of aggressive HER2-positive breast cancer;
  • sorafenib, often used to treat patients with kidney cancer;
  • erlotinib, widely used in the treatment of non-small cell lung cancer.

Currently, the authors are engaged in planning clinical trials, the purpose of which will be to study the effectiveness of the use of kinase inhibitors in increased dosages. Breaks are planned between taking such dosages, which will reveal the advantages and disadvantages of the method being studied. They hope that the revealed potential of the known drugs will allow to suspend the progression of malignant tumors for much longer periods than currently achievable.

Article by Sigrun Polier et al. ATP-competitive inhibitors block protein kinase recruitment to the Hsp90-Cdc37 system is published in the journal Nature Chemical Biology.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the University of Sussex:
Sussex scientist unlocks hidden potential of cutting-edge cancer drugs.


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