Abstract
Melanoma is the most aggressive type of skin cancer and resistance to the conventional chemotherapy is the major cause for its poor prognosis. Metabolic perturbations leading to increased production of reactive oxygen species activate NRF2-dependent anti-oxidative responses to survive oxidative stress. This protective function of NRF2 is the primary cause for therapy resistance in cancer as anti-cancer agents such as BRAF inhibitors also induce NRF2-dependent antioxidative response. We had reported that type I interferons produced upon activation of STING, abrogates NRF2 function. Therefore, we investigated if STING agonists such as the newly developed dimeric aminobenzimidazole (diABZI) could sensitize melanoma cells to the clinically used BRAF inhibitors. Our results reveal that pharmacological activation of STING by diABZI, down regulates NRF2-dependent anti-oxidative responses and potentiates cell-death in melanoma cells when used in combination with BRAF inhibitors.
Highlights
Melanoma is the most aggressive type of skin cancer and is responsible for most skin cancer related deaths [1]
We investigated the effect of dimeric aminobenzimidazole (diABZI), the novel small molecule Stimulator of interferon genes (STING) agonist in C32 melanoma cells harboring BRAF600VE mutation and are moderately resistant to BRAF inhibitor (BRAFi) [19]
Since we observed that diABZI potently activates STING pathway and prevents NRF2 activation, we investigated if the combination of diABZi with the currently available BRAFis; Dabrafenib and Vemurafenib will activate STING and inhibit NRF2
Summary
Melanoma is the most aggressive type of skin cancer and is responsible for most skin cancer related deaths [1]. BRAF mutation is involved in various mechanisms of melanoma progression but predominantly hyperactivates downstream MEK/ERK pathway [3]. Surgical excision, targeted therapy, immunotherapy and chemotherapy are the current therapeutic options for the melanoma patients [4]. Targeted therapies include BRAF and MEK inhibitors. Vemurafenib, was the first FDA approved specific BRAF inhibitor (BRAFi) [3]. Dabrafenib, another BRAFi was approved by FDA which has higher potency and fewer side effects than Vemurafenib [5]. These two specific BRAFis show excellent clinical response with substantial reduction of tumor burden in the initial stages. The long-term success is compromised due to the development of drug resistance [6]
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