Melanoma is one of the most frequent tumours in young adults. Even though it only accounts for 4% of all cases of skin cancer, melanoma is responsible for 79% of all skin cancer-related deaths. Despite the progress that has been made in the treatment of melanoma (e.g. with BRAF inhibitors), patients finally succumb due to resistance mechanisms acquired by the tumour. Many lines of evidence have shown that especially a metastatic melanoma exhibits a strong metabolic turnover, which is required to fuel cell proliferation and anabolic pathways. This increased cellular turnover also results in an increased demand to maintain the redox homeostasis. Here we propose analysing this high metabolic and therefore also ROS (reactive oxygen species) generating stress as a possible Achilles heel of melanoma. One of the major regulators of stress response in cancer is NRF2. It plays a central role in the protection of cells against oxidative and xenobiotic stresses.
The inhibition of NRF2 or its target genes might re-establish the sensitivity of melanoma to apoptosis driven by ROS. This mechanism could also prevent resistance mechanisms frequently observed in metastatic melanoma and may eliminate the frequently observed activation of endothelial cells, which surround tumour cells. It is highly likely that a combination of state of the art melanoma treatment with compounds that inhibit the generation of ROS scavengers potentiates the effectiveness of the current treatment regiments. Here we will use CRISPR-based methods as well as pharmacological inhibition to elucidate the mechanistic role of NRF2 in melanoma cells and on endothelial cells. We will also Transfer knowledge gained from our model by closely cooperating with clinicians who routinely care for melanoma patients. We propose that eliminating the antioxidative response by suppressing NRF2 directly, or its targets, will be an effective weapon in the battle against metastatic melanoma.
The project is funded by NÖ Forschungs- und Bildungsges.m.b.H (NFB).