A06
Targeting the oxidative stress response of non-small cell lung cancers
Project Summary
Cancer cells rewire metabolic networks to consistently supply energy and building blocks for cell division and rapid proliferation. This energy demand produces harmful by-products, including reactive oxygen species (ROS), which damage macromolecules and impair cancer cell viability. To maintain redox homeostasis, cancer cells enhance their antioxidative response system. Approximately 30% of non-small cell lung cancers (NSCLC) have mutations that prevent proteasomal degradation of nuclear factor erythroid 2-related factor 2 (NRF2), the key regulator of the cellular antioxidant response. Aberrant NRF2 activity drives cancer progression, metastasis, and therapy resistance in NSCLC. Despite NRF2 being a promising therapeutic target, direct pharmacological inhibition has proven to be challenging.
We hypothesize that the oxidative stress response in NSCLC could alternatively be targeted by inhibiting deubiquitylases (DUBs) that regulate NRF2 activity. We aim to identify DUBs that deubiquitylate and stabilize NRF2 or control NRF2 activity independent of its proteasomal degradation. Inhibition of these DUBs is a promising strategy to counteract elevated NRF2 activity in NSCLC.
