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

• 批准号: 10608045
• 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
• 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/10608045
• 关键词: Acute Myelocytic Leukemia; Affect; Blood; Bone Marrow; Cell Death; Cell Proliferation; Cell membrane; Cells; Cytoplasm; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Disorder; DNA Repair Pathway; DNA-dependent protein kinase; DNMT3a; Data; Defect; Disease; Disease Progression; Disease remission; Double Strand Break Repair; Epigenetic Process; FLT3 gene; Foundations; Gene Mutation; Genes; Genetic; Genomic Instability; Hematopoietic Neoplasms; Human; Immunologic Deficiency Syndromes; 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; Poly(ADP-ribose) Polymerase Inhibitor; Proliferating; Protein Tyrosine Kinase; Refractory; Reporting; Research; Resistance; Role; Sampling; Stem cell transplant; Testing; Therapeutic; Therapeutic Effect; Tyrosine Kinase Inhibitor; Update; Work; Xenograft procedure; 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; stem cells; therapeutic evaluation; therapy outcome; tumor; tumor initiation

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）。