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AZD9291 belongs to a class of drugs known as tyrosine kinase inhibitors. It works by blocking the function of a protein called the epidermal growth factor receptor (EGFR). The EGFR is found on the surface of many cancer cells as well as normal cells. It serves as an “antenna”, receiving signals from other cells and the environment that tell the cell to grow and divide. The EGFR plays an important role in growth and development during early life and helps to maintain normal levels of division to replace old and damaged cells in the adult. However, many cancer cells have inordinately large amounts of the EGFR on their surface, or their EGFR has been altered by mutation of the DNA that codes for the protein. The result is that the signals coming from the EGFR are much too strong, leading to excessive cell growth and division, a hallmark of cancer.
How does AZD9291 work?
When the EGFR receives a signal, it transmits it into the cell by causing a chemical reaction that modifies other proteins. The portion of the EGFR protein that carries out this function is called the tyrosine kinase domain. The ability of the tyrosine kinase domain of the EGFR to modify other proteins is critical to the EGFR’s ability to signal cells to grow and divide. This led researchers to look for a drug that attaches to the EGFR tyrosine kinase domain, blocking its ability to function. AZD9291 does just that.
How will AZD9291 be used in the clinic?
AZD9291 is a very new drug. It is currently being evaluated in clinical trials as a treatment for a subset of patients with advanced non-small cell lung cancer. The patients for which AZD9291 is being studied have lung cancer that was previously treated with an EGFR inhibitor such as erlotinib or gefitinib and whose cancer has started to re-grow after that therapy. Patients who initially respond to erlotinib or gefitinib have cancers that carry a particular kind of mutation that results in an abnormal EGFR protein. These patients are most likely to be of Asian descent, women, and never smokers with a form of lung cancer known as bronchoalveolar carcinoma. Usually, these patients initially respond well to therapy with erlotinib or gefitinib, but then the cancer eventually develops resistance. AZD9291 is directed specifically to these resistant tumors.
How is AZD9291 different from gefitinib and erlotinib?
The most common way that tumors develop resistance to gefitinib or erlotinib is by acquiring a second mutation that prevents the drugs from binding to the protein. AZD9291 is different from gefitinib and erlotinib in that it can bind to and block EGFR proteins bearing the most common resistance mutation.
What is the status of AZD9291?
AZD9291 is currently in phase I clinical trials. This is the earliest stage of clinical testing, in which the primary focus is on drug safety, including determination of a safe dosage range and identifying side effects. Although the main point of phase I trials is not to determine the effectiveness of the drug, Astra Zeneca, the manufacturer, has released statements suggesting that the drug is showing some promising results in patients. More information about clinical trials can be found at http://clinicaltrials.gov/ct2/about-studies/learn. Specific information about the AZD9291 trail can be found here http://clinicaltrials.gov/show/NCT01802632.