Department of Hematology, Tokyo Women's Medical University, Tokyo, Japan.
Department of Physiology and Cell Biology, Graduate School of Medicine and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
JCI Insight. 2016 Apr 21;1(5):e85061. doi: 10.1172/jci.insight.85061.
Multiple myeloma (MM) is a relapsed and refractory disease, one that highlights the need for developing new molecular therapies for overcoming of drug resistance. Addition of panobinostat, a histone deacetylase (HDAC) inhibitor, to bortezomib and dexamethasone improved progression-free survival (PFS) in relapsed and refractory MM patients. Here, we demonstrate how calcineurin, when inhibited by immunosuppressive drugs like FK506, is involved in myeloma cell growth and targeted by panobinostat. mRNA expression of , a catalytic subunit of calcineurin, was high in advanced patients. Panobinostat degraded PPP3CA, a degradation that should have been induced by inhibition of the chaperone function of heat shock protein 90 (HSP90). Cotreatment with HDAC inhibitors and FK506 led to an enhanced antimyeloma effect with a greater PPP3CA reduction compared with HDAC inhibitors alone both in vitro and in vivo. In addition, this combination treatment efficiently blocked osteoclast formation, which results in osteolytic lesions. The poor response and short PFS duration observed in the bortezomib-containing therapies of patients with high suggested its relevance to bortezomib resistance. Moreover, bortezomib and HDAC inhibitors synergistically suppressed MM cell viability through PPP3CA inhibition. Our findings underscore the usefulness of calcineurin-targeted therapy in MM patients, including patients who are resistant to bortezomib.
多发性骨髓瘤（MM）是一种复发性和难治性疾病，这突出表明需要开发新的分子疗法来克服耐药性。在硼替佐米和地塞米松的基础上添加 panobinostat（一种组蛋白去乙酰化酶（HDAC）抑制剂），可改善复发性和难治性 MM 患者的无进展生存期（PFS）。在这里，我们证明了当钙调神经磷酸酶被免疫抑制剂如 FK506 抑制时，它如何参与骨髓瘤细胞的生长，并被 panobinostat 靶向。在晚期患者中，钙调神经磷酸酶的一个催化亚基 的 mRNA 表达水平较高。panobinostat 降解了 PPP3CA，这种降解本应是由热休克蛋白 90（HSP90）的伴侣功能抑制诱导的。与单独使用 HDAC 抑制剂相比，HDAC 抑制剂和 FK506 的联合治疗在体外和体内均导致 PPP3CA 减少更多，从而增强了抗骨髓瘤作用。此外，这种联合治疗还能有效阻止破骨细胞的形成，从而导致溶骨性病变。在含有硼替佐米的疗法中，高表达 的患者反应较差且 PFS 持续时间较短，表明其与硼替佐米耐药有关。此外，硼替佐米和 HDAC 抑制剂通过 PPP3CA 抑制协同抑制 MM 细胞活力。我们的研究结果强调了钙调神经磷酸酶靶向治疗在 MM 患者中的实用性，包括对硼替佐米耐药的患者。
