A CRISPR approach to develop pro-oxidant therapies for lung cancer

Lung cancer is one of the most common cancer forms with poor prognosis for patients with advanced disease.

Evidence from our group and others suggest that lung cancer cells are damaged by oxidative stress and that reactive oxygen species can be an ally in the fight against cancer. Our goal is to develop new cancer therapies targeted against endogenous antioxidants.

The CRISPR-CAS9 technology has opened up new opportunities for genome-wide knockout screens in human cells, often in combination with drug perturbations.

Data from such screens can reveal mechanisms of drug effects and new drug targets for combination therapies that enhance the drug effect in a synthetic lethal fashion.

We have made two important discoveries that we will exploit in this proposal: First, by performing a genome-wide CRISPR-CAS9 screen of pro-oxidant drugs, we found that activation of WNT signalling pathways in lung cancer cells was synthetic lethal with buthionine sulfoximine (BSO), a glutamyl-cysteine ligase inhibitor that has shown to be well tolerated in phase I clinical trials.

The finding raises the possibility that BSO treatment kills WNT-driven tumors in a synthetic lethal manner.

Second, we found that deprivation of amino acids sensitizes lung cancer cells to BSO, a finding that opens up for using protein restricted diets as cancer therapies.

In this program, we will uncover the mechanisms involved and validate the clinical relevance, in mouse and patient-derived tumor models