# VS-4718 enhances apoptosis induced by low-dose carfilzomib and overcomes carfilzomib resistance in PSMB5-mutated proteasome inhibitor resistant multiple myeloma

## TL;DR

VS-4718 combined with low-dose carfilzomib effectively reduces multiple myeloma cell survival and overcomes drug resistance.

## Contribution

VS-4718 enhances carfilzomib's anti-tumor effect and overcomes resistance in proteasome inhibitor-resistant multiple myeloma.

## Key findings

- VS-4718 reduced viability in all parental human MM cell lines in a concentration-dependent manner.
- Combining VS-4718 with low-dose carfilzomib showed more than additive anti-tumor effects with minimal toxicity to healthy cells.
- VS-4718 re-sensitized resistant MM cells to carfilzomib, reducing cell survival more than either drug alone.

## Abstract

The introduction of proteasome inhibitors (PIs) into multiple myeloma (MM) treatment has substantially improved therapeutic options and survival rates. However, the development of resistance to PIs as well as serious side effects of PI treatment continue to justify the search for effective, less burdensome combination therapies. Thus, we investigated the therapeutic potential of VS-4718 (dual pPYK2- and pFAK-inhibitor) alone and in combination with the PI carfilzomib (carf) in parental human MM cell lines (pHMCLs) and PI triple-resistant HMCLs (rHMCLs). VS-4718 reduced the viability in a concentration dependent manner in all pHMCLs and the response was independent of PYK2 expression or activation. A more than additive impact of the combination therapy on survival, measured by annexin V-FITC/PI staining, was observed in 5/7 pHMCLs. Titration experiments showed that VS-4718 in combination with low and sublethal doses of carf had a specific anti-tumor effect on pHMCLs but hardly affected peripheral blood mononuclear cells. In rHMCLs, addition of VS-4718 to carf re-sensitized cells to carf and revealed a more than additive reduction in cell survival. These findings suggest that VS-4718 together with low doses of carf could be an effective and low-toxic combination in MM, including PI-resistant, relapsed/refractory MM.

The online version contains supplementary material available at 10.1038/s41598-026-43205-4.