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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要 Ras/MAPK 通路在 85% 的人类癌症中被激活，但仍尝试以 Ras/MAPK 为靶点。我们抓住了失败的原因之一。靶向该途径的原因是靶向工作集中于该级联中激酶的活性位点，我们再次认识到，这种方法的失败有两个原因。原因：1）活性位点抑制剂，类似于三磷酸腺苷（ATP），必须克服过度的癌细胞中的高胞质 ATP 水平；2) 该级联中的关键激酶（例如 ERK1/2）具有独特的特征底物相互作用域可以在调节癌症进展中发挥拮抗作用。经过测试，活性部位集中抑制类似于同时踩下加速器和制动器我们渴望更成功的方法是开发抑制剂保留激酶活性，但将其专门转移到“制动踏板”底物上，我们已经证明了这一点。 ERK2 的两个底物结合域（称为 D 域和 DPB 域）在 JAK2 激酶驱动的骨髓增生性肿瘤 (MPN) 的发病机制确实是 DBP 和 D 结构域起作用。就像刹车踏板和油门踏板一样，分别阻止和促进疾病进展。加速踏板（D 域）或其底物的药理衰减应损害肿瘤进展比活性位点抑制更有效，因为它选择性地干扰促进疾病的活性 ERK2，同时保留 DBP 结构域的肿瘤抑制功能，同时我们有令人信服的证据。对于 ERK2-D 和 DBP 结构域的相反作用，其作用的分子基础仍不清楚这阻碍了针对 ERK2 D 结构域的有效性、药理学干预措施的发展。现在，我们将根据以下目标寻求解决这一知识差距：1）评估普遍性。 ERK2-D 和 DBP 结构域在不同 MPN 亚型发病机制中的相反功能；了解 ERK2-D 和 DBP 结构域发挥其独特功能的机制基础；3) 评估 ERK2-D 结构域和/或其靶标的药物靶向抑制癌症的功效通过这些努力，我们期望为 ERK2 底物结合的作用带来新的见解我们首先讨论调节癌症进展的模块以及如何利用这些信息进行治疗。 MPN，这些发现可能对其他 Ras/MAPK 驱动的癌症具有深远的影响。