Atraric acid increases the antitumor effect of BRAF inhibitor through the regulation of the HGK/MEK1/ERK signaling pathway.

Abstract

Malignant melanoma is the most aggressive and deadly skin cancer. Conventional treatment drugs, such as vemurafenib, are prone to resistance, resulting in very low patient survival. This study probed into the antitumor potential of coadministration of atraric acid (AA), a natural compound derived from lichens with multiple biological activities, and vemurafenib in melanoma. Our findings revealed that AA enhances vemurafenib's ability to reduce viability and induce apoptosis in B16-F10 melanoma cells. In vivo studies, including histological analysis, showed that the combination of AA and vemurafenib effectively inhibited melanoma growth and metastasis with minimal side effects. Inhibition of tumor growth by vemurafenib in the presence of AA increased from 20.11% to 23.93% (low dose AA) and 52.06% (high dose AA). Transcriptomic analysis, quantitative reverse transcription polymerase chain reaction, and western blot indicated that AA enhances the antimelanoma effect of vemurafenib was mediated through the modulation of hematopoietic progenitor kinase 1 (HGK), MAP kinase kinase 1 (MEK1), and extracellular signal-regulated kinase (ERK) expression. Molecular docking studies suggested that AA might reduce the expression of MEK1 and ERK by suppressing the phosphorylation of HGK, thereby enhancing vemurafenib inhibition of melanoma growth and metastasis. In conclusion, our study presents AA as a promising candidate that may help enhance the antimelanoma activity of vemurafenib, offering a new avenue for clinical cancer treatment. SIGNIFICANCE STATEMENT: The combination of atraric acid and vemurafenib effectively inhibited melanoma growth and metastasis with minimal side effects. The synergistic effect of atraric acid and vemurafenib is achieved by suppressing the phosphorylation of HGK to reduce the expression of MEK1 and ERK. Atraric acid is a promising candidate in combating chemoresistance in melanoma therapy.