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Tyrosine kinases are proteins that play essential roles in biologic pathways that lead to cell growth, differentiation and survival. Because they mediate such critical cellular pathways, genetic alterations to kinases are often associated with cancer.
Genetic alterations refer to changes in the normal DNA sequence of a particular gene. Genes provide the instructions to make proteins, such as tyrosine kinases, that signal and control how cells in the body function. Each gene has a unique DNA sequence or code - these are the instructions for making proteins. When the genetic code is altered, dysfunctional and abnormally activated proteins may be produced resulting in cancer. Abnormally activated and dysfunctional proteins may dysregulate normal biologic processes and cells to multiply and become cancerous.
Alterations in tyrosine kinase genes occur often, but not all of these alterations are created equal. Some may have no negative consequences while others can be drivers of cancer. For example, mutations of the MET gene are found in nearly 60% of lung cancers. However, only about 10% of MET mutations are believed to actually be driving mutations that cause lung cancer. Mirati's tyrosine kinase inhibitor, Glesatinib (MGCD265), targets specific MET mutations and amplifications as well as AXL fusions believed to be drivers in 7-8% of non-small cell lung cancers.
The genetic alterations involving tyrosine kinases and the response of cancer patietns exhibiting genetic alterations to targeted therapies indicates that tyrosine kinases are attractive drug targets. Targeted drugs, such as Glesatinib and Sitravatinib (MGCD516), are designed to bind to and inhibit specific tyrosine kinases found on the surface of cells, blocking or reversing the abnormal signaling that is causing cancer. Patients with genetic mutations in certain tyrosine kinases can be readily identified by genomic profiling of their tumors using advanced DNA sequencing technologies. Genomic testing of tumor cells allows oncologists to match a patient's genetic abnormalities to a specific targeted therapy so that the patient receives a treatment that is most likely to be effective.