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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).

致癌性酪氨酸激酶（OTKs）如FLT 3（ITD）和JAK 2（V617 F）诱导急性髓系白血病白血病（AML）和骨髓增生性肿瘤（MPN）。OTK可以是伴有“另外的”突变（例如，TET 2、DNMT 3A）遗传/表观遗传并发症签名.选择性OTK抑制剂（OTKi）是针对FLT 3（ITD）阳性AML开发的， JAK 2（V617 F）阳性MPN，但OTKi治疗患者中完全缓解罕见，在最初的反应之后，疾病通常进展到更恶性的阶段。 FLT 3（ITD）阳性AML和JAK 2（V617 F）阳性MPN蓄积致死性DNA双链，链断裂（DSB）。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- NHEJ）。HR和D-NHEJ修复增殖细胞中的DSB，并且D-NHEJ在增殖细胞中起主要作用。静止细胞PARP 1依赖性备份NHEJ（B-NHEJ）在增殖和静止细胞FLT 3（ITD）和JAK 2（V617 F）阳性AML/MPN干细胞通常具有耐药性因为这些OTK调节DNA修复途径以促进存活。 DSB修复中的癌症特异性缺陷创造了使用合成杀伤力的机会，例如通过PARP抑制剂（PARPi）消除BRCA 1/2突变的癌细胞。我们报道了 OTKis诱导HR和D-NHEJ缺陷，其使静止和增殖的 FLT 3（ITD）/JAK 2（V617 F）阳性AML/MPN干细胞对PARPi引发的合成致死性的影响。然而，我们最近的报告和初步数据强烈表明，“额外” 突变（例如，在TET 2中，DNMT 3A）可改变FLT 3（ITD）和JAK 2（V617 F）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FLT 3（ITD）和JAK 2（V617 F）敏感性的“额外”突变和机制- 阳性细胞对OTKi+ PARPi介导的合成致死性的反应。我们还报道并获得了骨髓微环境（BMM）诱导对OTKi + PARPi处理的抗性。因此，我们将查明与BM相关的 OTKi + PARPi介导的合成致死性的障碍，并将BMM抑制剂（BMMi）应用于具体目标#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目标#3中的合成致死效应的突变。治疗 OTKi + PARPi +/- BMMi对携带特异性“驱动”突变的AML/MPN的作用 [FLT 3（ITD/TKD），JAK 2（V617 F）]和“另外的”突变（例如，TET2）。