NT157 has antineoplastic effects and inhibits IRS1/2 and STAT3/5 in JAK2V617F-positive myeloproliferative neoplasm cells.,Signal Transduction and Targeted Therapy

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NT157 has antineoplastic effects and inhibits IRS1/2 and STAT3/5 in JAK2V617F-positive myeloproliferative neoplasm cells.
Signal Transduction and Targeted Therapy ( IF 40.8 ) Pub Date : 2020-01-24 , DOI: 10.1038/s41392-019-0102-5
Bruna Alves Fenerich _{1,

2} , Jaqueline Cristina Fernandes _{1,

2} , Ana Paula Nunes Rodrigues Alves _{1,

2} , Juan Luiz Coelho-Silva _{1,

2} , Renata Scopim-Ribeiro _{1,

2} , Priscila Santos Scheucher ₁ , Christopher A Eide _{3,

4} , Cristina E Tognon _{3,

4} , Brian J Druker _{3,

4} , Eduardo Magalhães Rego _{1,

2,

5} , João Agostinho Machado-Neto _{1,

6} , Fabiola Traina _{1,

2}

Affiliation

Recent data indicate that IGF1R/IRS signaling is a potential therapeutic target in BCR-ABL1-negative myeloproliferative neoplasms (MPN); in this pathway, IRS2 is involved in the malignant transformation induced by JAK2V617F, and upregulation of IGF1R signaling induces the MPN phenotype. NT157, a synthetic compound designed as an IGF1R-IRS1/2 inhibitor, has been shown to induce antineoplastic effects in solid tumors. Herein, we aimed to characterize the molecular and cellular effects of NT157 in JAK2V617F-positive MPN cell lines (HEL and SET2) and primary patient hematopoietic cells. In JAK2V617F cell lines, NT157 decreased cell viability, clonogenicity, and cell proliferation, resulting in increases in apoptosis and cell cycle arrest in the G2/M phase (p < 0.05). NT157 treatment inhibited IRS1/2, JAK2/STAT, and NFκB signaling, and it activated the AP-1 complex, downregulated four oncogenes (CCND1, MYB, WT1, and NFKB1), and upregulated three apoptotic-related genes (CDKN1A, FOS, and JUN) (p < 0.05). NT157 induced genotoxic stress in a JAK2/STAT-independent manner. NT157 inhibited erythropoietin-independent colony formation in cells from polycythemia vera patients (p < 0.05). These findings further elucidate the mechanism of NT157 action in a MPN context and suggest that targeting IRS1/2 proteins may represent a promising therapeutic strategy for MPN.

中文翻译：

NT157 具有抗肿瘤作用，可抑制 JAK2V617F 阳性骨髓增殖性肿瘤细胞中的 IRS1/2 和 STAT3/5。

最近的数据表明，IGF1R/IRS 信号传导是 BCR-ABL1 阴性骨髓增生性肿瘤 (MPN) 的潜在治疗靶点；在该通路中，IRS2参与JAK2V617F诱导的恶性转化，IGF1R信号传导的上调诱导MPN表型。 NT157 是一种设计为 IGF1R-IRS1/2 抑制剂的合成化合物，已被证明可在实体瘤中诱导抗肿瘤作用。在此，我们的目的是表征 NT157 在 JAK2V617F 阳性 MPN 细胞系（HEL 和 SET2）和原代患者造血细胞中的分子和细胞作用。在 JAK2V617F 细胞系中，NT157 降低细胞活力、克隆形成和细胞增殖，导致细胞凋亡增加和细胞周期停滞在 G2/M 期 (p < 0.05)。 NT157 治疗抑制 IRS1/2、JAK2/STAT 和 NFκB 信号传导，并激活 AP-1 复合物，下调四种癌基因（CCND1、MYB、WT1 和 NFKB1），上调三种凋亡相关基因（CDKN1A、FOS、和六月）（p < 0.05）。 NT157 以不依赖 JAK2/STAT 的方式诱导基因毒性应激。 NT157 抑制真性红细胞增多症患者细胞中不依赖促红细胞生成素的集落形成（p < 0.05）。这些发现进一步阐明了 NT157 在 MPN 中的作用机制，并表明靶向 IRS1/2 蛋白可能代表了一种有前途的 MPN 治疗策略。

更新日期：2020-01-24

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