Tyrosine kinase inhibitors: application of chemical and discovery proteomics to the problem of chemotherapeutic toxicity in cancer patients

 Conventional chemotherapy for numerous cancers involves toxic and damaging drugs that cause severe side effects in patients. Scientists have for decades searched for the ‘magic bullet’ that would target only cancer cells, thereby reducing or eliminating the toxic effects of treatment. While this has yet to be fully achieved, huge strides have been made in the development of more specific drugs. One example of this is the group of tyrosine kinase inhibitors (TKIs).

Osimertinib is a TKI used to treat lung cancer in patients with mutations in their epidermal growth factor receptor (EGFR). The drug binds irreversibly to the receptor, thereby limiting EGF-stimulated proliferation. Despite the improved targeting of the drug compared to earlier therapies, many patients receiving TKIs develop severe liver and gastrointestinal (GI) toxicity, limiting the utility of the drug and impairing the quality of life for patients. Toxicity is believed to be a consequence of irreversible binding of the drug/metabolites to proteins other than the intended targets (off-target toxicity). This project will use cutting-edge technology to identify the off-target proteins, to decipher the consequences and potential mitigation of off-target binding, and to chemically engineer better drugs for the future.

The study will be carried out using human liver and GI organoids. These are mini organs-in-a-test-tube that mimic many of the functions of cells or tissues in the body. They are becoming increasingly vital to the study of disease and drug safety because they outperform conventional cell culture methods and they don’t require animal models. You will be trained on all aspects of organoid generation and maintenance.

To apply to this project, email your CV and cover letter to the primary supervisor: r.jenkins@liverpool.ac.uk