Target the Dusp1 in Jak2 dependent myeloproliferative neoplasm (MPN) for curative treatment

针对 Jak2 依赖性骨髓增生性肿瘤 (MPN) 中的 Dusp1 进行治愈性治疗

• 批准号: 10655109
• 负责人: Mohammad Azam
• 金额: $ 22.51万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655109
• 关键词: Ablation; Acceleration; Cell Death Induction; Cells; Clinic; DUSP1 gene; Development; Disease; Failure; Feedback; Genetic; Granulocyte Colony-Stimulating Factor Receptors; JAK2 gene; Leukemic Cell; MAP Kinase Gene; MAPK phosphatase; Mediating; Mediator; Molecular; Mutation; Myeloproliferative disease; Patients; Philadelphia Chromosome; Phosphotransferases; Population; Regulation; Relapse; Research; Residual Neoplasm; Resistance; Signal Transduction; Specimen; Structure; Tyrosine Kinase Inhibitor; anticancer treatment; cancer cell; clinical application; curative treatments; inhibitor; inhibitor therapy; insight; kinase inhibitor; leukemia initiating cell; mouse model; mutant; oncogene addiction; overexpression; pharmacologic; response; treatment response

Despite the impressive response to tyrosine kinase inhibitor (TKI) therapy in the clinic as an anti-cancer treatment, it is not curative. Even the most potent kinase inhibitors are ineffective against a small population of cancer cells, which are insensitive to treatment; manifesting as minimal residual disease (MRD). Likewise, myeloproliferative disorders treated with Jak2 inhibitors show intrinsic resistance to TKI treatment . Failure eradicate the persistent cells them leads to post-therapy relapse. Therapeutic response to TKI is mediated by oncogene-addiction; however, the molecular mechanisms governing TKI-induced cell death in the context of oncogene-addiction is not clearly understood. We find that MAPK phosphatase, Dusp1, is a critical mediator of oncogene-addiction in MPD driven by mutations in JAK2, MPL and CSF3R. Overexpression of Dusp1 in MPDs abrogates oncogene addiction and ablates TKI response. Both genetic and pharmacological inhibition of Dusp1 is synthetic lethal to Jak2-V761F and CSF3R-T618I driven MPDs. The proposed research will address the sensitivity of murine-model of MPD leukemia initiating cells and primary patient specimens to disrupting Dusp1 activity alone and in the context of TKI therapy. In addition, we propose to develop specific and potent Dusp1 inhibitor using structure function studies for clinical application. Our results should accelerate development of a curative therapy for MPDs.

尽管酪氨酸激酶抑制剂（TKI）作为一种抗癌药物在临床上取得了令人印象深刻的反应 治疗，它没有疗效。即使是最有效的激酶抑制剂也对小分子无效。 对治疗不敏感的癌细胞群；表现为微小残留病 （MRD）。同样，用 Jak2 抑制剂治疗的骨髓增殖性疾病显示出内在的耐药性 TKI治疗。未能根除持久性细胞会导致治疗后复发。治疗性 对 TKI 的反应是由癌基因成瘾介导的；然而，控制的分子机制 致癌基因成瘾背景下 TKI 诱导的细胞死亡尚不清楚。我们发现 MAPK 磷酸酶 Dusp1 是 MPD 中癌基因成瘾的关键介质，由突变驱动 JAK2、MPL 和 CSF3R。 MPD 中 Dusp1 的过度表达可消除癌基因成瘾并消除 TKI 反应。 Dusp1 的遗传和药理学抑制对 Jak2-V761F 具有合成致死作用 和 CSF3R-T618I 驱动的 MPD。拟议的研究将解决小鼠模型的敏感性 MPD 白血病起始细胞和原发性患者标本单独破坏 Dusp1 活性， 在 TKI 治疗的背景下。此外，我们建议开发特异性且有效的 Dusp1 抑制剂 将结构功能研究用于临床应用。我们的成果应该加速发展 MPD 的一种治疗方法。