Sorafenib sensitizes melanoma cells to vemurafenib through ferroptosis

Abstract

Background: BRAF gene mutation causes melanoma patients to develop drug resistance after 8-9 months BRAF inhibitors treatment. Therefore, overcoming BRAF inhibitor resistance has important implications for improving patient survival. Sorafenib directly inhibits tumor cell proliferation by blocking the RAF/MEK/ERKmediated cell signaling pathway. It remains unknown that whether the combination of sorafenib with vemurafenib could sensitize melanoma cells to vemurafenib, and the underlying mechanism needs to be clarified.Methods: Vemurafenib resistant melanoma cells A375/Vem and SK-Mel-28/Vem were established by exposing to a series of concentration of vemurafenib. Cell viability was measured when A375 and SK-Mel-28 cells treated with vemurafenib or combined with sorafenib. Meanwhile the levels of Iron, GSH, MDA and reactive oxygen species (ROS) were detected. Finally we examined that whether sorafenib sensitizes melanoma cells to vemurafenib through ferroptosis.Results: We found that sorafenib sensitized melanoma cells to vemurafenib. Sorafenib treatment did not significantly alter the production of ROS and the content of iron, GSH and MDA in vemurafenib resistant cells, but cotreatment of sorafenib and vemurafenib dramatically upregulated ROS production, MDA and iron, but decreased GSH concentration. Interestingly, sorafenib strongly promoted vemurafenibinduced cell death, which was blocked by lipid peroxidation inhibitors ferrostatin-1 but not ZVAD-FMK or necrosulfonamid.Conclusions: Sorafenib sensitized melanoma cells to vemurafenib by increasing ROS production through ferroptosis. Our study reveals that the combination of sorafenib may provide a novel strategy of vemurafenib resistant melanoma therapy.

DeepDDS: deep graph neural network with attention mechanism to predict synergistic drug combinations

“…Also, the combination of Erlotinib and Regorafenib in the treatment of hepatocellular carcinoma successfully overcome the interference of epidermal growth factors (DAlessandro et al, 2015). Addition of Sorafenib to Vemurafenib increased ROS production through ferroptosis, thus increasing the sensitivity of melanoma cells to vemurafenib (Tang et al, 2020). Zhang et al reproted that the Regorafenib combined with the Lapatinib could improve anti-tumor efficacy in human colorectal cancer (Zhang et al, 2017).…”

“…The famous pharmaceutical company AstraZeneca (Menden et al, 2019) released their drug pair collaboration experiments, which includes 11,576 experiments of 910 drug combinations to 85 cancer cell lines with genome-related information. DrugCombDB (Liu et al, 2020) has collected more than 6,000,000 quantitative drug dose responses, by which they calculated synergy scores to evaluate synergy or antagonism for each drug combination. In addition, quite a few data portal designed to collect drug combinations and relevant knowledge have been developed.…”

YY1 Is a Key Player in Melanoma Immunotherapy/Targeted Treatment Resistance

“…Interestingly, sorafenib may sensitize melanoma to vemurafenib through activation of oxidative stress (upregulated reactive oxygen species production, malondialdehyde, and iron, but decreased glutathione concentration). Moreover, sorafenib strongly promoted vemurafenib-mediated cell death ( 67 ).…”

Extracellular vesicles promote migration despite vemurafenib treatment in malignant melanoma cells

“…In preclinical experiments, vemurafenib increases cell death [30], [31], decreases proliferation [32], [33] and also affects cell migration [34]- [36]. Furthermore, exposure to vemurafenib can also modify the released EVs' content [37], [38].…”