Divergent Functions of ERK Substrate Binding Domains in Pathogenesis of Myeloproliferative Neoplasms

ERK 底物结合域在骨髓增生性肿瘤发病机制中的不同功能

• 批准号: 10719088
• 负责人: TOMASZ SKORSKI
• 金额: $ 70.7万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-06 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719088
• 关键词: Active Sites; Address; Adenosine Triphosphate; Attenuated; Automobiles; Binding; CBL gene; CRISPR screen; Candidate Disease Gene; Cell Culture Techniques; Clustered Regularly Interspaced Short Palindromic Repeats; DNA Repair; Data; Disease; Disease Progression; Docking; F Box Domain; Failure; Growth; Health; Human; Impairment; In Vitro; Intervention; JAK2 gene; Knock-in Mouse; Knowledge; MAP Kinase Gene; MAPK1 gene; MAPK3 gene; Malignant - descriptor; Malignant Neoplasms; Mediating; Mental Depression; Modeling; Molecular; Mutant Strains Mice; Myeloproliferative disease; Oncogenes; Oncogenic; PTPN11 gene; Pathogenesis; Pathway interactions; Phosphotransferases; Play; Polycythemia Vera; RUNX1 gene; Role; Series; Signal Transduction; Site; Substrate Interaction; Testing; Therapeutic; Therapeutic Intervention; Validation; Work; Xenograft Model; attenuation; cancer cell; candidate identification; driver mutation; efficacy evaluation; genetic approach; in vivo; in vivo Model; inhibitor; insight; melanoma; mutant mouse model; novel; novel therapeutic intervention; pharmacologic; preservation; restraint; senescence; small molecule; targeted treatment; therapeutically effective; time use; tumor; tumor progression; ubiquitin ligase

PROJECT SUMMARY/ABSTRACT The Ras/MAPK pathway is activated in 85% of human cancer. Nevertheless, attempts to target Ras/MAPK signaling have produced only limited efficacy. We hypothesize that one reason for the failure to successfully target this pathway is that the targeting efforts have focused on the active sites of kinases in this cascade, which has failed to provide long-lasting benefit. We hypothesize that the failure of this approach results from two causes: 1) Active site inhibitors, which resemble adenosine triphosphate (ATP), must overcome the exceedingly high cytosolic ATP levels in cancer cells; and 2) critical kinases in this cascade (e.g., ERK1/2) have distinct substrate interactions domains that can perform antagonistic roles in regulating cancer progression. Consequently, active-site focused inhibition is akin to simultaneous depression of the accelerator and brake pedals of an automobile. We hypothesize that a more successful approach will be to develop inhibitors which preserve kinase activity, but divert it exclusively to “brake pedal” substrates. In support, we have demonstrated that the two substrate binding domains of ERK2, termed the D and DPB domains, play opposing roles in the pathogenesis of JAK2-kinase driven myeloproliferative neoplasms (MPN). Indeed, the DBP and D domains act like brake and accelerator pedals, opposing and promoting disease progression, respectively. Consequently, pharmacologic attenuation of the accelerator pedal (D-domain) or its substrates should impair tumor progression more potently than active site inhibition, because it selectively interferes with the disease promoting activity of ERK2, while preserving the tumor suppressive function of the DBP-domain. While we have compelling evidence for the opposing roles of the ERK2-D and DBP domains, the molecular basis for their action remains unclear and this is an impediment to developing effective, pharmacologic interventions focused on the ERK2 D domain. We now seek to address this gap in knowledge according to the following aims. We will: 1) Assess the generality of the opposing functions of the ERK2-D and DBP domains in the pathogenesis of distinct MPN subtypes; 2) Understand the mechanistic basis by which the ERK2-D and DBP domains exert their distinct functions; and 3) Assess the efficacy of pharmacologic targeting of the ERK2-D domain and/or its targets in inhibiting cancer progression. Through these efforts we expect to bring new insights into the role of ERK2 substrate binding modules in regulating cancer progression and how to exploit this information therapeutically. While we begin with MPN, these findings may have far reaching implications for other Ras/MAPK driven cancers.

项目摘要/摘要 RAS/MAPK途径在85％的人类癌症中被激活。但是，尝试针对RAS/MAPK 信号传导仅产生有限的效率。我们假设失败的原因之一 针对这一途径的目标是，目标工作集中在该级联的激酶的活跃位点，该级联酶的活跃位点 未能提供持久的好处。我们假设这种方法的失败来自两个 原因：1）类似于三磷酸腺苷（ATP）的活性位点抑制剂必须克服更大的 癌细胞中的高胞质ATP水平； 2）此级联反应中的临界激酶（例如，ERK1/2）具有独特的 可以在控制癌症进展中扮演拮抗作用的底物相互作用域。 因此，主动部位的抑制类似于加速器和制动器的简单抑郁症 汽车的踏板。我们假设一种更成功的方法将是开发抑制剂 保留激酶活性，但仅将其转移到“制动踏板”底物上。为了支持，我们已经证明了 ERK2的两个底物绑定域称为D和DPB域，在 JAK2-激酶的发病机理驱动骨髓增生性肿瘤（MPN）。确实，DBP和D域行为 像制动和加速踏板一样，分别对立和促进疾病进展。最后， 加速器踏板（D域）或其底物的药理学衰减应损害肿瘤进展 比主动部位抑制更重要，因为它选择性地干扰了促进疾病的活动 ERK2，同时保留DBP域抑制肿瘤抑制功能。尽管我们有令人信服的证据 对于ERK2-D和DBP域的相对角色，其作用的分子基础尚不清楚 这是开发有效的药物干预措施的障碍，该干预措施集中在ERK2 D领域。 现在，我们寻求根据以下目的来解决知识的差距。我们将：1）评估一般性 ERK2-D和DBP结构域在不同MPN亚型的发病机理中的相反功能； 2） 了解ERK2-D和DBP域具有不同功能的机械基础； 3） 评估ERK2-D结构域和/或其靶标在抑制癌症方面的药理学靶向效率 进展。通过这些努力，我们希望将新的见解带入ERK2底物约束的作用 控制癌症进展的模块以及如何热利用此信息。当我们从 MPN，这些发现可能对其他RAS/MAPK驱动器取消具有很大的影响。