文章：

多发性骨髓瘤中IGF1R基因突变的功能性研究

Functional Investigation ofIGF1RMutations in Multiple Myeloma

原文发布日期：4 June 2024

DOI: 10.3390/cancers16112139

类型: Article

开放获取: 是

英文摘要：

High expression of the receptor tyrosine kinase (RTK) insulin-like growth factor-1 receptor (IGF1R) and RTK mutations are associated with high-risk/worse prognosis in multiple myeloma (MM). Combining the pIGF1R/pINSR inhibitor linsitinib with the proteasome inhibitor (PI) bortezomib seemed promising in a clinical trial, but IGF1R expression was not associated with therapy response. Because the oncogenic impact ofIGF1Rmutations is so far unknown, we investigated the functional impact ofIGF1Rmutations on survival signaling, viability/proliferation and survival response to therapy. We transfected four human myeloma cell lines (HMCLs) withIGF1RWT,IGF1RD1146NandIGF1RN1129S(Sleeping Beauty), generated CRISPR-Cas9IGF1Rknockouts in the HMCLs U-266 (IGF1RWT) and L-363 (IGF1RD1146N) and tested the anti-MM activity of linsitinib alone and in combination with the second-generation PI carfilzomib in seven HMCLs.IGF1Rknockout entailed reduced proliferation. Upon IGF1R overexpression, survival signaling was moderately increased in all HCMLs and slightly affected byIGF1RN1129Sin one HMCL, whereby the viability remained unaffected. Expression of IGF1RD1146Nreduced pIGF1R-Y1135, especially under serum reduction, but did not impact downstream signaling. Linsitinib and carfilzomib showed enhanced anti-myeloma activity in six out of seven HMCL irrespective of theIGF1Rmutation status. In conclusion,IGF1Rmutations can impact IGF1R activation and/or downstream signaling, and a combination of linsitinib with carfilzomib might be a suitable therapeutic approach for MM patients potentially responsive to IGF1R blockade.

摘要翻译： 

受体酪氨酸激酶（RTK）胰岛素样生长因子-1受体（IGF1R）的高表达及其突变与多发性骨髓瘤（MM）的高风险/不良预后相关。临床试验中，pIGF1R/pINSR抑制剂林西替尼与蛋白酶体抑制剂（PI）硼替佐米的联合应用前景良好，但IGF1R表达与治疗反应无明确关联。鉴于IGF1R突变的致癌机制尚不明确，本研究系统探讨了IGF1R突变对生存信号传导、细胞活力/增殖及治疗反应的影响。通过Sleeping Beauty转染系统，我们在四种人多发性骨髓瘤细胞系（HMCLs）中分别导入IGF1R野生型、IGF1R D1146N及IGF1R N1129S突变体；利用CRISPR-Cas9技术在U-266（IGF1R野生型）和L-363（IGF1R D1146N突变）细胞系中构建IGF1R敲除模型；并在七种HMCLs中评估林西替尼单药及与第二代PI卡非佐米联用的抗骨髓瘤活性。 实验结果显示：IGF1R敲除导致细胞增殖能力下降。IGF1R过表达时，所有HMCLs的生存信号传导均呈中度增强，其中一种HMCL的IGF1R N1129S突变对信号传导产生轻微影响，但细胞活力未受影响。IGF1R D1146N突变表达会降低pIGF1R-Y1135磷酸化水平（尤其在血清浓度降低条件下），但对下游信号传导无显著影响。在七种HMCLs中，有六种细胞无论IGF1R突变状态如何，林西替尼与卡非佐米联用均表现出协同抗骨髓瘤活性。 结论表明：IGF1R突变可影响IGF1R活化及下游信号传导；对于可能响应IGF1R阻断治疗的MM患者，林西替尼与卡非佐米联合疗法具有潜在临床应用价值。

原文链接：

Functional Investigation ofIGF1RMutations in Multiple Myeloma