Glutathione-dependent reprogramming in melanoma and its impact on therapy

• Applicant: Professorin Dr. Svenja Meierjohann
• Subject Area: Dermatology ; Cell Biology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 432439324

The therapy of malignant melanomas is currently based on two pillars: One therapy option is the inhibition of BRAF and MEK, which applies for melanoma patients carrying the driver mutation BRAF-V600E/K. The second option is the treatment with checkpoint inhibitors, which reactivate the immune system against the tumor. Together, these therapeutic strategies improve the overall survival of 40-65% of melanoma patients. Unfortunately, pre-existing or acquired resistance mechanisms cause disease progression in a large percentage of patients. Remarkably, a phenotypic switch from a dedifferentiated to a more mesenchymal-like gene signature is associated with resistance towards BRAF/MEK as well as checkpoint inhibitor resistance, indicating common escape strategies of the tumor cells.We have established in previous studies that the depletion of the intracellular antioxidant glutathione, e.g. by cystine depletion or inhibition of glutathione (GSH) synthesis, causes a similar phenotypic switch in melanoma and goes along with a downregulation of differentiation genes and an upregulation of mesenchymal genes as well as increased migration and invasion. This effect is mediated by the stress-inducible transcription factor ATF4. The proposed project focuses on the effect of GSH depletion and ATF activation on therapeutic success in melanoma. We have developed a mouse melanoma model with inducible GSH synthesis in the melanomas, allowing us to monitor tumor growth and therapy success in absence or presence of tumor GSH. Using this model, melanomas will be treated with BRAF/MEK or checkpoint inhibitors, and the phenotypic switch as well as tumor development will be followed over time. Chemotherapeutic agents were also reported to reduce glutathione levels in many cases, thus providing a risk for the phenotypic switch. However, chemotherapeutic agents are discussed as partners for immune therapy, with the hope to improve response to checkpoint inhibitor treatment. In particular, data from our group and other laboratories show that the glutaminase inhibitor CB839 as well as cisplatin reduce glutathione and induce ATF4. Both drugs are currently in preparation for clinical trials in combination with anti-PD-L1 antibodies in solid tumors. However, this might pose a risk, as our preliminary data indicate that the selection of resistant mesenchymal-type cell populations might be enhanced by CB839 or cisplatin. We therefore plan to mimick this therapeutical combination in the mouse model with particular focus on the formation of mesenchymal-type melanoma cells and a possible improved therapeutic effect in presence of inhibitors of the ATF4 induction. The link between GSH depletion, ATF4 induction and cellular reprogramming will then be investigated in molecular studies. These data will provide valuable biological insights into novel therapy options, with high relevance for the choice of drug combinations in current and future therapy approaches applied in the clinic.

• DFG Programme: Research Grants