Cancer-associated mutations are known to stabilize the transcription factor, NRF2, that controls the expression of genes involved in cellular antioxidant defense systems, which shield DNA and other vital molecules from highly reactive molecules called reactive oxygen species (ROS). In a Molecular Cell paper published in October, Ludwig Harvard Co-director Joan Brugge and colleagues reported their analysis of how NRF2 contributes to cancer cell growth and survival in experiments using lung cancer spheroid models—cultured, three-dimensional mimics of tumors. Their studies showed that its hyperactivation is required for both proliferation and survival of spheroid cultures, though distinct signaling pathways control each outcome. A pathway mediated by mTOR supports proliferation. As for survival, NRF2 activity protects cancer cells within the spheroid that are deprived of contact with the extracellular matrix from a type of programmed cell death known as ferroptosis, which is mediated by ROS. But when cells lack NRF2, a critical suppressor of ferroptosis, GPX4, and related proteins are expressed at high levels. Joan and her team show that inhibiting both NRF2 and GPX4 leads to the death of cancer spheroids. The results reveal a vulnerability in tumors dependent on NRF2 hyperactivation that might be targeted for the development of novel cancer therapies.
This article appeared in the April 2021 issue of Ludwig Link. Click here to download a PDF (1.4 MB).