Overcoming melanoma resistance to targeted therapy and immune checkpoint inhibitors

With 5-year survival rates for patients with metastatic disease around 30%, cutaneous melanoma is the leading cause of skin cancer related deaths. Standard of care for melanoma envisage a combination of BRAF and MEK inhibitors, a viable option only for melanoma patients carrying BRAF mutations, or immunotherapy. Both strategies are very efficient, however not all the patients respond to the treatment and often the responses are only transient. It is therefore very important to explore novel therapeutic strategies to overcome or delay the acquisition of resistance. Towards this, we recently demonstrated that targeting the lncRNA SAMMSON, inhibits mitochondrial translation and severely impairs melanoma cell growth in vitro and in vivo. In addition, recent findings indicate that the mitochondrial translation machinery is overexpressed upon development of resistance to immunotherapy, thus suggesting that the pathway could be a vulnerability of these cells. Since mitochondrial ribosomes closely resemble the bacterial ones, mitochondrial protein synthesis can be blocked with antibiotics. Antibiotics have been already proposed for the treatment of AML and Lymphomas, and clinical trials are currently ongoing. We have already evidence that combining antibiotics with MAPK inhibition is effective at eradicating BRAF mutant melanoma in PDX models. In light of the above, we would like to propose antibiotic treatment as a way to prevent the occurrence of resistance to multiple therapies.