Contribution by NRF2 upregulation to lung carcinogenesis, and the possible therapeutic value of NRF2 inhibition by GSK-3

点击翻译按钮获取中文摘要

In the UK about 41,000 individuals are diagnosed with lung cancer each year. It is the major cause of death from malignant disease worldwide. Therapeutic options for treating lung cancer are limited. It is now recognised that lung cancer patients ought to be treated in an individualized manner according to the genes that have been mutated and are responsible for development of their own tumour. In order to do this, biomarkers that reflect mutations in cancer-associated genes are required to guide clinicians in their choice of therapy. It has recently been discovered that mutations causing permanent activation of a master regulator of cellular antioxidant systems, called NRF2, are the 2nd and 4th most frequent events in the two major forms of lung cancer, but as NRF2 regulates many processes besides antioxidant systems it is uncertain why its upregulation might benefit the tumour (to the detriment of the patient). In this project we will identify mechanisms by which NRF2 upregulation aids development of lung cancer. We will also identify biomarkers associated with NRF2 that can be used by clinicians to identify tumours in which its upregulation contributes to the disease.An important related question is that we do not know whether inhibiting NRF2 hinders development of lung cancer, and addressing this issue is frustrated by the lack of drugs that inhibit NRF2. We recently found NRF2 can be suppressed in lung cancer cells by switching on a kinase, called GSK-3, which triggers destruction of NRF2. In our experiments, we activated GSK-3 in cell lines using a drug called MK2206. We now want to use mice to test whether MK2206 can be employed to inhibit NRF2 within lung tumours in vivo.The overarching objective of this grant is to assess whether the permanent activation of NRF2 can be exploited clinically in lung cancer.The first aim is to establish how NRF2 upregulation aids lung cancer by examining whether it supports it by: 1) increasing antioxidants and preventing cell death caused by high levels of oxidants produced as byproducts of tumour-specific activities; 2) increasing the ability of chemicals in tobacco smoke to cause mutations by converting them to DNA-damaging derivatives; 3) increasing synthesis of cellular macromolecules by providing more NADPH; 4) increasing cellular activity by providing more energy in the form of ATP.The second aim is to identify specific genes, small molecules and proteins within lung tumours that are altered as a consequence of NRF2 upregulation to explain how it aids lung tumour development, by using state-of-the art technologies to examine lung tumours created genetically in mice with incrementally varied levels of NRF2 [from none to large increases]. We will then utilize changes in these molecules as biomarkers of NRF2-directed processes that facilitate cancer.The third aim is to establish the clinical prognostic significance of the increase in NRF2 and the biomarker proteins it controls using antibodies to probe a well-characterized panel of human lung tumours.The fourth aim is to test in a mouse lung cancer model whether suppression of NRF2 by MK2206 decreases growth of lung tumours.This grant will increase our understanding of how NRF2 contributes to the development of lung cancer. It is of direct relevance to patients with lung cancer as identification of tumours in which NRF2 is upregulated will help predict the outcome of disease. Moreover, the ability to identify lung tumours with upregulated NRF2 and overexpression of its target genes will provide biomarkers for the personalized treatment of cancer that will be of great value to clinicians treating lung cancer patients. The grant will also allow us to test if pharmacological suppression of NRF2 using MK2206 inhibits growth of tumours lacking KEAP1. Importantly, MK2206 is already in clinical trials for lung cancer, providing the exciting prospect that our findings might be translated rapidly into the clinic.