Chemical proteomics reveals the dynamic rewiring of kinase networks in response to targeted MEK inhibition
New kinase test may yield big gains for drug-resistant cancers
- Date : 23 Apr 2012
- Topic : Pathology/Molecular biology
In a paper published on 13 April in the journal Cell, a team of researchers from the University of North Carolina at Chapel Hill unveiled the first broad-based test for activation of protein kinases "en masse", enabling measurement of the mechanism behind drug-resistant cancer and rational prediction of successful combination therapies.
Kinases are proteins expressed in human tissues that play a key role in cell growth, particularly in cancer. Of the 518 known human kinases, about 400 are expressed in cancers, but which ones and how many are actually active in tumours has been difficult to measure. Tremendous efforts have been made to develop kinase inhibitors as cancer treatments, which have resulted in key drugs such as trastuzumab, lapatinib, and imatinib. However, in spite of the effectiveness of this class of cancer drugs, most cancers eventually become resistant.
Using a quantitative proteomics approach, the University of North Carolina’s team assessed kinome activity in response to MEK inhibition in triple-negative breast cancer cells and genetically engineered mice. Key findings from their work are:
- Inhibition of the MEK-ERK pathway rapidly reprogrammes kinome activity in tumours
- c-Myc degradation induces expression and activation of receptor tyrosine kinases
- Receptor tyrosine kinase activation overcomes MEK inhibition, causing resistance
- Kinome inhibitor response profiling rationally predicts combination therapies
The test can measure both the presence and activity of 60-70% of all kinases simultaneously, allowing investigators to see how cancers evade treatment with kinase inhibitors so that they can combine drugs to block resistance.
The researchers are excited about the ability to examine tumour samples before, during, and after kinase inhibitor treatment to see how the tumour kinase profile changes, and potentially respond to those changes using different inhibitors.
The team hopes to be able to track and define the kinase reprogramming that takes place in tumours during therapy and to use the new test to identify combinations of drugs that will block the cancer's adaptive behaviour that leads to drug resistance. A patent application has been filed for the testing technology.
The research was funded by the National Institute for General Medical Sciences (USA) and accelerated by two ARRA grants. It was initially funded with an innovation award from the University of North Carolina Lineberger University Cancer Research Fund and has also been supported by developmental funds from University of North Carolina’s NCI-sponsored Specialized Programme of Research Excellence (SPORE) in Breast Cancer and the Breast Cancer Research Foundation.
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