DataSheet1_SHP2 Inhibitors Show Anti-Myeloma Activity and Synergize With Bortezomib in the Treatment of Multiple Myeloma.pdf

Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. The protein tyrosine phosphatase SHP2 is a central node regulating RAS/mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK) signaling pathway which plays a crucial role in the pathogenesis and proteasome inhibitor (PI) resistance of MM. Several preclinical studies have demonstrated that SHP2 inhibitors exerted antitumor activity in cancer-harboring diverse mutations in the RAS pathway, offering the potential for targeting myeloma. In this study, we showed that pharmacological inhibition of SHP2 activity using SHP099 and RMC-4550 efficiently inhibited the proliferation of MM cells by inducing apoptosis and cell cycle arrest. As per the mechanism, SHP2 inhibitors activated the level of cleaved caspase3, BAK, and P21 and downregulated ERK phosphorylation in MM cells. Moreover, the blockade of SHP2 exhibited anti-myeloma effect in vivo in a mouse xenograft model. In addition, SHP2 inhibitors synergized the antineoplastic effect of bortezomib in bortezomib-sensitive MM cells and showed identical efficacy in targeting bortezomib-resistant MM cells. Overall, our findings suggest that SHP2-specific inhibitors trigger anti-myeloma activity in vitro and in vivo by regulating the ERK pathway and enhancing cytotoxicity of bortezomib, providing therapeutic benefits for both bortezomib naïve and resistant MM.

多发性骨髓瘤（Multiple Myeloma, MM）是一种至今仍无法治愈的浆细胞恶性肿瘤。蛋白酪氨酸磷酸酶SHP2（protein tyrosine phosphatase SHP2）是调控RAS/丝裂原活化蛋白激酶（mitogen-activated protein kinase, MAPK）/细胞外信号调节激酶（extracellular signal regulated kinase, ERK）信号通路的核心节点，该通路在多发性骨髓瘤的发病机制与蛋白酶体抑制剂（proteasome inhibitor, PI）耐药中发挥关键作用。多项临床前研究已证实，SHP2抑制剂对携带RAS通路多种突变的癌症具有抗肿瘤活性，为靶向治疗骨髓瘤提供了潜在可能。本研究采用SHP099与RMC-4550对SHP2活性进行药理学抑制，结果显示该手段可通过诱导细胞凋亡与细胞周期阻滞，有效抑制多发性骨髓瘤细胞的增殖。机制研究表明，SHP2抑制剂可上调多发性骨髓瘤细胞中裂解型半胱氨酸天冬氨酸蛋白酶3（cleaved caspase3）、BAK与P21的表达水平，并下调ERK的磷酸化水平。此外，在小鼠异种移植模型中，阻断SHP2可在体内发挥抗骨髓瘤效应。进一步研究发现，SHP2抑制剂可在硼替佐米敏感型多发性骨髓瘤细胞中协同增强硼替佐米的抗肿瘤效应，且在硼替佐米耐药型多发性骨髓瘤细胞中亦表现出同等的治疗效果。综上，本研究结果表明，特异性SHP2抑制剂可通过调控ERK通路、增强硼替佐米的细胞毒性，在体内外发挥抗骨髓瘤活性，可为硼替佐米初治与耐药型多发性骨髓瘤患者带来治疗获益。