Small molecule treatments for EGFR inhibitor resistant lung cancer

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.

Epidermal growth factor receptor (EGFR) signalling is a key oncogenic driver. A significant proportion of non-small cell lung cancer (NSCLC), in particular, is driven by sensitising mutations in EGFR (L858R and Exon 19del). EGFR kinase inhibitors (e.g. erlotininib, gefitinib) are effective treatments but ultimately resistance develops, commonly through further mutations in the kinase domain involving T790M. More recent therapies, most notably osimertinib, are efficacious in treating T790M resistant disease and osimertinib is also becoming an established first line and adjuvant therapy. Osimertinib is a covalent inhibitor that targets C797 in EGFR, and resistance to treatment often arises through further mutations that affect this covalent mechanism, most commonly C797S. There is currently no available treatment for C797S mutated lung cancer. We have identified compounds that are capable of inhibiting growith of EGFR mutant tumour cell lines including those that carry C797S osimertinib resistance mutations.
The compounds posess the properties of drug-like small molecules and their technical profiles and SAR give confidence that they are optimisable leads. A robust test casade involving enzyme assays, mechanistic and phenotypic cell assays and structural biology is in place to enable optimisation. In this project, we will opsimise the compounds to deliver an in vivo active compound for in vivo target validation.