Scholarlink

<p>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月16日

查看全文
  • Ellen Leich-Zbat,
  • Sofia Catalina Heredia-Guerrero,
  • Marietheres Evers,
  • Thorsten Stühmer,
  • Tina Grieb,
  • Hilka Rauert-Wunderlich,
  • Ralf C. Bargou,
  • Andreas Rosenwald,
  • Manik Chatterjee,
  • Daniela Brünnert

摘要

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.