PO-219 Methylglyoxal-induced dicarbonyl stress: role in melanoma progression and response to therapy

Introduction Methylglyoxal (MG) is an endogenous dicarbonyl spontaneously produced during glycolysis able to react with proteins, lipids and DNA, inducing a carbonyl stress. Glyoxalase 1 (GLO1) detoxifies MG into D-Lactate. High MG is notably associated with diabetes and cancer. Melanoma is the most deadly form of skin cancer. Therapy is notably based on the inhibition of the MAPK pathway, often over activated. Unfortunately, BRAF and MEK inhibitors are briefly efficient as tumours rapidly develop resistance mechanisms. Melanoma tumours are generally highly glycolytic and therefore inevitably produce high amounts of MG, accumulating Advanced Glycation End products (AGEs). Phenformin, a metformin analogue with MG-scavenging properties, improves the therapeutic effect of BRAF inhibition. This observation is in good accordance with our hypothesis that MG could be involved in progression and resistance of melanoma. Material and methods This study aims to assess the metabolic profile of various human melanoma cell lines comprising BRAF and/or MEK inhibitors sensitive and resistant cells. First, we plan to explore thoroughly dicarbonyl stress status in these cell lines and in patient tissues. Next, we will subject melanoma cells to anti-carbonyl stress agents such as l-carnosine and aminoguanidine alone or in combination with MAPK pathway inhibitors and assess their effect on tumour cell survival. Results and discussions IHC staining of argpyrimidines, MG-derived AGEs, in a collection of melanoma samples showed that MG carbonyl stress is a constant feature in melanoma. MG AGEs were detectable in both BRAF inhibitors sensitive and resistant cell lines: A375 and A2058, respectively. Interestingly, the treatment of these cells with exogenous MG induced different responses: A375 cells increased their MG detoxification system and their metabolic activity as assessed by their increased GLUT1 and GLUT3 glucose transporters and PGC1alpha mitochondrial regulator. Whereas, A2058 resistant melanoma cells showed a decrease of both GLO1 activity and the metabolic markers investigated. Conclusion Ongoing experiments will help to understand these phenotypes and to further characterise a serie of WT and BRAF mutated melanoma cells. We plan to assess carbonyl stress in a larger human melanoma collection to investigate the correlation with tumour stage, metastasis, overall survival and resistance to therapy. Finally, we will test the efficacy of a combined therapy using BRAF and/or MEK inhibitors and MG scavenger molecules such as carnosine.