NHE6-driven endosome-autophagy axis confers proteasome inhibitor resistance in multiple myeloma

Aims: Proteasome inhibitors (PIs) play a central role in multiple myeloma (MM) therapy; however, a substantial proportion of patients fail to achieve durable responses, resulting in early disease progression and limited long-term clinical benefit. This paper aims to understand the molecular mechanisms that constrain PI efficacy and drive resistance and explore a novel strategy for improving therapeutic outcomes in MM.

Methods: By integrative analysis of multiple publicly available transcriptomic datasets from large MM patient cohorts, we identified sodium-hydrogen exchanger 6 (NHE6), encoded by SLC9A6. This gene emerged as a candidate gene associated with resistance to PI-based therapy. Functional studies were performed using patient-derived primary MM cells, PI-resistant MM cell lines, and preclinical mouse models.

Results: NHE6 is highly expressed in MM cells with further upregulation in PI-nonresponsive disease. Elevated NHE6 expression is associated with reduced progression-free and overall survival. We demonstrate that NHE6 promotes acidification in the endosomal lumen, thereby facilitating early-to-late endosomal maturation and enhancing autophagic flux in MM cells. This process in turn attenuates PI-induced tumor cell apoptotic death. Consistent with this mechanism, genetic ablation or pharmacologic inhibition of NHE6 disrupted endosomal maturation, impaired Autophagy, and markedly increased sensitivity to bortezomib and carfilzomib in vitro and in vivo PI-resistant models.

Conclusions: These findings identify an NHE6-mediated endosomal-autophagy axis as a previously unrecognized mechanism of PI resistance in MM. Targeting NHE6 represents a promising upstream strategy to restore apoptotic responses to PI-based therapies and improve therapeutic outcomes in refractory MM.