Oncogenic tyrosine kinases inhibitors abrogate DNA repair and sensitive leukemias to PARP inhibitors

致癌酪氨酸激酶抑制剂可消除 DNA 修复和对 PARP 抑制剂敏感的白血病

基本信息

批准号：
10374000
负责人：
TOMASZ SKORSKI
金额：
$ 39.96万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10374000
关键词：
Acute Myelocytic Leukemia Affect Back Blood Bone Marrow Bone Marrow Stem Cell Cell Death Cell membrane Cells DNA Damage DNA Double Strand Break DNA Repair DNA Repair Disorder DNA Repair Pathway DNA-dependent protein kinase Data Defect Disease Disease remission Double Strand Break Repair Epigenetic Process FLT3 gene Foundations Gene Mutation Genes Genetic Genomic Instability Hematopoietic Neoplasms Human JAK2 gene Leukemic Cell Malignant - descriptor Malignant Neoplasms Mediating Modality Modeling Mus Mutate Mutation Myeloid Leukemia Myeloproliferative disease Nonhomologous DNA End Joining Normal Cell Normal tissue morphology Oncogenic Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Play Proliferating Protein Tyrosine Kinase Refractory Reporting Research Resistance Role Sampling Stem cell transplant Testing Therapeutic Therapeutic Effect Tyrosine Kinase Inhibitor Update Work Xenograft procedure base brca gene cancer cell cancer stem cell chemotherapy driver mutation homologous recombination improved inhibitor leukemia leukemic stem cell news novel therapeutic intervention novel therapeutics peripheral blood prevent protective effect repaired response standard care stem cells therapeutic evaluation therapy outcome tumor

项目摘要

Oncogenic tyrosine kinases (OTKs) such as FLT3(ITD) and JAK2(V617F) induce acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs), respectively. OTKs may be accompanied by “additional” mutations (e.g., TET2, DNMT3A) complicating genetic/epigenetic signature. Selective OTK inhibitors (OTKi) are developed against FLT3(ITD)-positive AMLs and JAK2(V617F)-positive MPNs, but complete remissions were rare in OTKi-treated patients, and after initial response the disease progressed often in to more malignant stage. FLT3(ITD)-positive AMLs and JAK2(V617F)-positive MPNs accumulate lethal DNA double- strand breaks (DSBs). DSBs are repaired by two major mechanisms, BRCA-mediated homologous recombination (HR) and DNA-PK –mediated non-homologous end-joining (D- NHEJ). HR and D-NHEJ repair DSBs in proliferating cells and D-NHEJ plays a major role in quiescent cells. PARP1–dependent back-up NHEJ (B-NHEJ) works in proliferating and quiescent cells. FLT3(ITD) and JAK2(V617F)-positive AML/MPN stem cells are usually resistant to DSBs because these OTKs modulate DNA repair pathways to promote survival. Cancer-specific defects in DSB repair create the opportunity to employ synthetic lethality, e.g. elimination of BRCA1/2-mutated cancer cells by PARP inhibitor (PARPi). We reported that OTKis induce HR and D-NHEJ deficiencies, which sensitize quiescent and proliferating FLT3(ITD)/JAK2(V617F)-positive AML/MPN stem cells to synthetic lethality triggered by PARPi. However, our recent reports and preliminary data strongly suggest that “additional” mutations (e.g., in TET2, DNMT3A) can change FLT3(ITD) and JAK2(V617F)-positive AML/MPN cells sensitivity to OTKi + PARPi. Therefore in Specific Aim #1 we propose to identify “additional” mutations and mechanisms which affect sensitivity of FLT3(ITD) and JAK2(V617F)- positive cells to OTKi+PARPi-mediated synthetic lethality. We also reported and obtained preliminary data that bone marrow microenvironment (BMM) induces resistance to OTKi + PARPi treatment. Therefore we will pinpoint BMM-related obstacles for OTKi + PARPi-mediated synthetic lethality and apply BMM inhibitor (BMMi) in Specific Aim #2: Overcoming the protective effect of BMM against OTKi + PARPi treatment. Finally, we will test therapeutic potential of OTKi + PARPi +/- BMMi against AMLs/MPNs xenografts carrying mutations favoring synthetic lethal effect in Specific Aim #3. Therapeutic effect of OTKi + PARPi +/- BMMi against AMLs/MPNs carrying specific “driver” mutations [FLT3(ITD/TKD), JAK2(V617F)] and “additional” mutations (e.g., TET2).

致癌酪氨酸激酶 (OTK)，如 FLT3(ITD) 和 JAK2(V617F) 诱导急性髓系白血病可能分别是白血病 (AML) 和骨髓增生性肿瘤 (MPN)。伴随“额外”突变（例如 TET2、DNMT3A），使遗传/表观遗传复杂化选择性 OTK 抑制剂 (OTKi) 是针对 FLT3(ITD) 阳性 AML 开发的。 JAK2(V617F) 阳性 MPN，但在接受 OTKi 治疗的患者中完全缓解的情况很少见，并且在最初的反应之后，疾病常常进展到更恶性的阶段。 FLT3（ITD）阳性 AML 和 JAK2（V617F）阳性 MPN 积累致命 DNA 双倍链断裂 (DSB) 通过两种主要机制修复：BRCA 介导的。同源重组 (HR) 和 DNA-PK 介导的非同源末端连接 (D- HR 和 D-NHEJ 修复增殖细胞中的 DSB，D-NHEJ 在其中起重要作用。 PARP1 依赖性备用 NHEJ (B-NHEJ) 在增殖和增殖过程中发挥作用。 FLT3(ITD) 和 JAK2(V617F) 阳性 AML/MPN 干细胞通常具有耐药性。 DSB 是因为这些 OTK 调节 DNA 修复途径以促进生存。 DSB 修复中的癌症特异性缺陷为利用合成致死性创造了机会，例如，我们报道了 PARP 抑制剂 (PARPi) 消除 BRCA1/2 突变的癌细胞。 OTK 会导致 HR 和 D-NHEJ 缺陷，从而使静止和增殖细胞变得敏感 FLT3(ITD)/JAK2(V617F)阳性AML/MPN干细胞对PARPi触发的合成致死作用。然而，我们最近的报告和初步数据强烈表明“额外” 突变（例如，TET2、DNMT3A）可以改变 FLT3(ITD) 和 JAK2(V617F) 阳性 AML/MPN 细胞对 OTKi + PARPi 的敏感性因此在具体目标 1 中我们建议确定。影响 FLT3(ITD) 和 JAK2(V617F) 敏感性的“额外”突变和机制- OTKi+PARPi 介导的合成致死率阳性细胞。我们还报告并获得了骨髓微环境（BMM）的初步数据诱导对 OTKi + PARPi 治疗的耐药性，因此我们将查明与 BMM 相关的情况。克服 OTKi + PARPi 介导的合成致死的障碍并应用 BMM 抑制剂 (BMMi) 具体目标#2：克服 BMM 对 OTKi + PARPi 治疗的保护作用。最后，我们将测试 OTKi + PARPi +/- BMMi 针对 AML/MPN 的治疗潜力异种移植物携带有利于特定治疗目标#3中的合成致死效应的突变。 OTKi + PARPi +/- BMMi 对携带特定“驱动”突变的 AML/MPN 的影响 [FLT3(ITD/TKD)、JAK2(V617F)] 和“其他”突变（例如 TET2）。