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.

尽管对诊所的酪氨酸激酶抑制剂（TKI）的反应令人印象深刻 治疗，这是无法治愈的。即使是最有效的激酶抑制剂，对小的抑制剂也无效 对治疗不敏感的癌细胞种群；表现为最小残留疾病 （MRD）。同样，用JAK2抑制剂治疗的骨髓增生性疾病显示出对 TKI治疗。失败消除了它们的持续细胞导致疗法后复发。治疗性 对TKI的反应是由癌基因添加介导的；但是，管理的分子机制 TKI诱导的细胞死亡在癌基因添加的背景下尚不清楚。我们发现 MAPK磷酸酶DUSP1是由突变驱动的MPD中癌基因添加的关键介体 JAK2，MPL和CSF3R。 MPD中DUSP1的过表达消除了癌基因成瘾和灌溉 TKI响应。 DUSP1的遗传学和药理抑制作用均与JAK2-V761F合成 和CSF3R-T618I驱动的MPD。拟议的研究将解决鼠模型的敏感性 MPD白血病引发细胞和原发性患者标本，以破坏DUSP1活性和 在TKI疗法的背景下。此外，我们建议开发特定和有效的DUSP1抑制剂 使用结构功能研究进行临床应用。我们的结果应加速 MPD的治疗疗法。