Analysis of the role of NRF2 in ferroptosis modulation in chemotherapy-resistant tumor cell lines

Abstract

Chemotherapy resistance is the cause of failure in most patients with metastatic cancer. NRF2 is an important gene involved in chemotherapy resistance through its ability to regulate genes related to the antioxidant response, as well as prevent the cell from cell death processes, such as ferroptosis. Ferroptosis has been increasingly studied as an alternative in antitumor therapy. Ferroptosis-inducing agents approved by FDA have been shown to be effective for the treatment of kidney, liver, and thyroid cancer. However, the relationship between NRF2 and ferroptosis is still poorly understood. There are studies indicating that NRF2 and its targets expression could inhibit or even induce ferroptosis. Thus, in this PhD project we plan to investigate how NRF2 and its targets act in ferroptosis modulation in a wide range of tumor cell lines, in order to understand whether drug resistance can be reversed through collateral ferroptosis sensitivity. For doing that, we will select and establish chemotherapy-resistant tumor cell lines, then we will measure their sensitivity to ferroptosis and their expression of NRF2 and its targets. Next, we will knock out the ABCC1 and HMOX1 genes in the lines that express collateral sensitivity (CS) in order to investigate whether these genes mediate CS in these cells. Thus, it is expected that this project will contribute to improving our knowledge about chemotherapy resistance and the mechanism of induction of ferroptosis in several tumor cell lines, which will be very important to reverse chemotherapy resistance by ferroptosis induction in future clinical trials.