Novel pro-survival mechanisms of PIM2 in multiple myeloma

PIM2 在多发性骨髓瘤中的新的促生存机制

• 批准号: 10668651
• 负责人: KELVIN P. LEE
• 金额: $ 59.66万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668651
• 关键词: Acute Myelocytic Leukemia; Affect; American Cancer Society; Binding; Binding Proteins; Biological; Biological Assay; Bone Marrow; Bone Marrow Neoplasms; Cell Death; Cell Survival; Cells; Cessation of life; Code; Complex; Data; Development; Disease Progression; Down-Regulation; Family; Gene Expression; Genes; Genetic Transcription; Hematologic Neoplasms; Homeostasis; Malignant Neoplasms; Messenger RNA; Metabolism; Mitochondria; Modeling; Molecular; Multiple Myeloma; Non-Hodgkin' s Lymphoma; Oncogenes; Oncogenic; PIM1 gene; Pathogenesis; Patients; Phosphotransferases; Plasma Cells; Play; Production; Proliferating; Protein-Serine-Threonine Kinases; Proteins; Reactive Oxygen Species; Regulation; Regulatory Element; Reporting; Resistance; Respiration; Role; Serine; Signal Transduction; Small Interfering RNA; Solid; Solid Neoplasm; Source; Stimulus; Testing; Transactivation; Treatment Failure; Up-Regulation; Work; c-myc Genes; chemotherapeutic agent; constitutive expression; curative treatments; experimental study; fatty acid oxidation; inhibitor; kinase inhibitor; knock-down; mitochondrial metabolism; mutant; nanomolar; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; overexpression; programs; promoter; protein expression; proto-oncogene protein pim; response; therapeutic target; therapy resistant

Multiple myeloma (MM) comprises 20% of all hematologic malignancies, second only to non-Hodgkin’s lymphoma, with 34,470 new cases and 12,640 deaths expected in 2022. Despite new therapeutics, MM remains incurable for almost all patients. The primary cause of treatment failure is upregulation of pro-survival mechanisms and progressively greater therapy resistance - thus defining these pro-survival responses will identify key therapeutic targets. The PIM family of serine/threonine kinases (PIM1, PIM2 and PIM3) have been shown to be oncogenic and overexpressed in a wide range of solid and hematological malignancies, with the highest level of PIM2 overexpression seen with MM disease progression. PIM kinases are constitutively active, and because the mRNA and protein have short half-lives their biological activity is dictated by regulation of their expression. Importantly, it is currently assumed that biological effects of PIM kinases are entirely due to their kinase activity. Bringing this assumption into question, we recently reported that the first-in-class PIM2-selective non-ATP-competitive inhibitor JP11646 (JP) caused significantly greater suppression of MM proliferation and viability compared to ATP-competitive PIM kinase inhibitors that equivalently inhibited PIM2 kinase activity. We found that JP’s increased efficacy was not due to superior inhibition of kinase activity, but rather to an unexpected downregulation of PIM2 gene and protein expression that did not occur with the ATP-competitive PIM2 kinase inhibitors. These observations led to our central hypothesis that PIM2 has critical but previously unrecognized kinase-independent (Ki) pro-survival function in MM – including maintaining high constitutive expression of the PIM2 gene. Preliminary studies have found that kinase-dead PIM2 mutants retain significant pro-survival activity. Mechanistically, we found that PIM2 stably interacts with the oncogene cMYC in MM cells and increases cMYC binding to several gene promoters - including PIM2 itself. Moreover, a cMYC inhibitor downregulated PIM2 expression, suggesting a novel auto-regulatory loop where PIM2 stabilizes cMYC binding and trans-activation of the PIM2 promoter – JP, but not ATP-competitive PIM kinase inhibitors, disrupts this loop. Additionally, we found that SLC25A11 and UCP2 – two genes coding mitochondrial metabolite transporters – are regulated by PIM2-cMYC axis in MM. Consistent with this, JP treatment or PIM2 knockdown selectively disrupted oxidative mitochondrial respiration, which we show is dependent on fatty acid oxidation (FAO). We propose to test a novel model of SLC25A11 and UCP2 overexpression reprogramming MM metabolism to favor FAO and promoting MM survival. Since JP has similar effects in acute myeloid leukemia and in solid tumors, PIM2 Ki function in MM may also occur to other cMYC-driven cancers. As such, inhibition of PIM2 Ki function may be a broadly applicable approach to target oncogenic cMYC activity. The Specific Aims proposed are: 1). To determine the kinase- independent mechanisms by which PIM2 supports MM survival, 2). To elucidate PIM2 auto-regulation in MM cells, and 3).To establish how PIM2 regulates MM metabolism independent of its kinase activity. 1

多发性骨髓瘤（MM）占所有血液恶性肿瘤的20%，仅次于非霍奇金淋巴瘤