Small molecule treatments for EGFR inhibitor resistant lung cancer

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Describe the research in simple terms in a way that could be publicised to a general audience. If awarded, this will be made publicly available and applicants are responsible for ensuring that the content is suitable for publication.Non-small cell lung cancer is one of the most common forms of cancer. In about 30% of cases, it is driven by changes in a protein called epidermal growth factor receptor (EGFR). These mutations cause an increase in the signals that instruct the cancer cells to divide, invade tissues and spread through the body. EGFR is a receptor that spans the cell wall. Part of the protein on the inside of the cell, called the kinase domain, is responsible for transmitting these signals. To switch the signal on, two molecules of EGFR come together and the kinase domain promotes a chemical reaction that adds groups called a phosphates from one molecule to the other. This chemical modification switches on the cancer driving signals.Cancers that are driven by activated EGFR can be treated by drugs, called EGFR inhibitors, that bind to the kinase domain and stop the chemical reaction by blocking the binding of the molecules that provide the phosphate groups that are transferred. Perhaps the most successful drug currently is osimertinib (Tagrisso), which is able to effectively treat patients for a substantial period (about 1-2 years). However, inevitably the cancers become resistant the drug and disease progresses. In many cases, the resistance develops through further changes to the EGFR protein that mean that the drug can no longer effectively bind.Our project will develop new drug treatments that can effectively treat cancers that have become resistant to EGFR inhibitors like osimertinib. The new treatment will ultimately be used subsequently to EGFR inhibitor therapy and thus, in conjunction, will be expected to significantly extend the lives of non-small cell lung cancer patients.We have developed a set of molecules that are able to prevent the growth of cancer cells that have the common EGFR changes that make them resistant to EGFR inhibitors, including osimertinib. This current grant will allow us to take our promising leads and improve them to a point that they can be shown to stop resistant tumours growing in models of lung cancer and pave the way to further improvements to produce a molecule that can be progressed into clinical trials.