Investigating the mechanism of SHP2 and BCL2 Inhibition in Acute Myeloid Leukemia (AML)

项目总结/摘要 背景：受体酪氨酸激酶（RTK）信号基因突变，如Fms样 酪氨酸激酶3（FLT 3）和KIT原癌基因出现在三分之二的急性髓系白血病中。 白血病（AML），并与高复发率相关。FLT 3酪氨酸激酶抑制剂 （TKI）在FLT 3突变型AML中具有临床活性，但缓解持续时间受到以下因素的限制： 由于RAS信号传导的重新激活而产生抗性。没有具体的已证实的治疗方法 存在于这些复发患者或具有其他信号传导突变的患者中。理由： 蛋白酪氨酸磷酸酶SHP 2是RAS激活和增殖的中心节点， 生长因子信号SHP 2调节RTK下游的MAPK途径活化，但 SHP 2活性的完整分子机制尚不清楚。小分子变构抑制剂 SHP 2如RMC-4630稳定了SHP 2的闭合的、自抑制的构象，并且在 临床发展。本申请的目的是利用新的变构SHP 2抑制剂 （SHP 2 i），以阐明SHP 2在RTK介导的AML存活中的分子作用，并检测 SHP 2 i与BCL 2抑制剂（BCL 2 i）维奈托克组合的功效。方法：我们将 测试SHP 2 i与BCL 2 i组合在FLT 3和KIT突变AML中的治疗功效。 我们将使用单细胞多组测序来发现反应和耐药性的生物标志物。 利用生物化学和蛋白质组学方法，我们将评估SHP 2 i对RTK的影响 FLT 3和KIT突变AML细胞中的信号传导以及对细胞凋亡的相关影响。我们将 分离RAS/MAPK转录激活在SHP 2介导的存活中的作用， 确定SHP 2在RTK驱动的AML中粘附介导的存活信号传导中的作用。 预期结果：我们预计这些研究将揭示有关作用的新知识 SHP 2在白血病细胞存活中的作用，并促进SHP 2 i组合的合理开发 治疗，特别是与BCL 2 i的组合。这项工作的总体目标是发展 SHP 2抑制剂治疗作为RTK驱动的AML的新型治疗策略

PROJECT SUMMARY/ABSTRACT Background: Mutations in receptor tyrosine kinase (RTK) signaling genes such as Fms-Like Tyrosine Kinase 3 (FLT3) and the KIT proto-oncogene occur in two-thirds of acute myeloid leukemia (AML) and are associated with high relapse rates. FLT3 tyrosine kinase inhibitors (TKIs) are clinically active in FLT3-mutant AML but duration of response is limited by the development of resistance due to re-activation of RAS signaling. No specific proven therapy exists for these relapsed patients or patients with other signaling mutations. Rationale: The protein tyrosine phosphatase SHP2 is a central node in RAS activation and propagation of growth factor signals. SHP2 modulates MAPK pathway activation downstream of RTKs but the full molecular mechanisms of SHP2 activity are not clear. Small molecule allosteric inhibitors of SHP2 such as RMC-4630 stabilize the closed, autoinhibited conformation of SHP2 and are in clinical development. The goal of this application is to leverage new allosteric SHP2 inhibitors (SHP2i) to elucidate the molecular role of SHP2 in RTK-mediated survival in AML and test the efficacy of SHP2i in combination with the BCL2 inhibitor (BCL2i) venetoclax. Methods: We will test the therapeutic efficacy of SHP2i in combination with BCL2i in FLT3 and KIT mutant AML. We will use single cell multiomic sequencing to discover biomarkers of response and resistance. Using biochemical and proteomic approaches, we will assess the effect of SHP2i on RTK signaling in FLT3 and KIT mutant AML cells and associated effects on apoptosis. We will isolate the role of RAS/MAPK transcriptional activation in SHP2-mediated survival and determine the role of SHP2 in adhesion-mediated survival signaling in RTK-driven AML. Expected Results: We anticipate that these studies will uncover new knowledge about the role of SHP2 in leukemic cell survival and facilitate rational development of SHP2i combination therapies, particularly in combination with BCL2i. The overall goal of this work is to develop SHP2 inhibitor therapy as a novel treatment strategy in RTK-driven AML.