Activin A Secreted by Cancer-Associated Fibroblasts Reduces the Sensitivity of Breast Cancer Cells to Ixazomib via Inhibition of Proteasome Activity.

Breast cancer (BC) remains a leading cause of cancer-related mortality among women globally, and the role of cancer-associated fibroblasts (CAFs) in promoting BC progression is well established. Ixazomib, a proteasome inhibitor approved for the treatment of multiple myeloma, has demonstrated therapeutic potential in BC in preclinical trials. However, whether its efficacy is influenced by the tumor microenvironment, particularly CAFs, remains unclear. This study aims to investigate the role of CAFs with high expression of Activin A (encoded by INHBA) in modulating the sensitivity of BC cells to ixazomib. We demonstrate that ixazomib exhibited significant cytotoxicity in BC cells, but high-INHBA CAFs compromise ixazomib cytotoxicity through ERK-mediated proteasome suppression, reversible by Activin A antagonism. Additionally, the overexpression of INHBA in fibroblasts reduces the efficacy of ixazomib in xenograft models. Clinical data analysis revealed that high INHBA expression is associated with poor prognosis in BC patients and reduced immune cell infiltration. These findings suggest that targeting INHBA in CAFs could enhance the therapeutic efficacy of ixazomib in BC, particularly in patients with low INHBA expression. This study provides novel insights into the role of CAFs in drug resistance and identifies INHBA as a potential therapeutic target.