Modulation of Mcl-1 for Treatment of Lung Cancer

调节 Mcl-1 治疗肺癌

基本信息

批准号：
10612924
负责人：
Xingming Deng
金额：
$ 42.52万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612924
关键词：
Animal Cancer Model Antineoplastic Agents Apoptotic Attenuated BRCA mutations Biological Cancer Etiology Cancer Model Cancer cell line Clinical Combined Modality Therapy DNA Double Strand Break DNA Repair DNA Repair Pathway DNA Sequence Alteration DNA biosynthesis Data Development Down-Regulation FDA approved Family member Genetic Engineering Goals Growth Human Immunotherapy In Vitro KRAS2 gene Link MAPK3 gene MCL1 gene MEKs Malignant Neoplasms Malignant neoplasm of lung Mediating Mutation Non-Small-Cell Lung Carcinoma Oncogenic Outcome PD-1 blockade PD-1 inhibitors PI3K/AKT Pathway interactions Patients Phosphorylation Phosphorylation Site Play Poly(ADP-ribose) Polymerase Inhibitor Prognosis Prognostic Marker Proteins Reporting Resistance Resistance development Role STK11 gene Signal Transduction Subgroup TP53 gene Therapeutic Therapeutic Intervention Tumor Tissue Up-Regulation Xenograft procedure anti-PD-1/PD-L1 anti-PD-L1 anti-PD-L1 therapy anti-cancer cancer cell cancer therapy homologous recombination improved in vivo inhibitor lung cancer cell mortality mutant new therapeutic target novel objective response rate overexpression patient subsets potency testing programmed cell death ligand 1 radioresistant refractory cancer replication stress small molecule survival outcome synergism targeted treatment therapeutic target therapy resistant tumor tumor growth

项目摘要

Summary KRAS mutations activate Raf/MEK/ERK1/2 that can directly phosphorylate Mcl-1 at T163, enhancing Mcl-1’s function. KRAS mutations also activate PI3K/AKT that can inactivate GSK-3 and inhibit GSK-3-mediated pMcl-1 at S159 to reduce Mcl-1 degradation. We hypothesize that KRAS mutation-activated ERK1/2 and PI3K/AKT pathways contribute to stabilization of Mcl-1 via upregulation of pMcl-1 at T163 and downregulation of pMcl-1 at S159 in lung cancer. Our preliminary data show increased pMcl-1 at T163 in tumor tissues from NSCLC patients, which associated with worse survival outcome, suggesting that pMcl-1 at T163 may provide a new therapeutic target and a prognostic biomarker in NSCLC patients. We found that Mcl-1, in addition to its canonical antiapoptotic function, plays a critical role in supporting homologous recombination (HR)-mediated repair of DNA double-strand breaks (DSBs). Based on this novel function, we discovered an entirely new class of small molecule Mcl-1 inhibitor, MI-223, that interacts with the BH1 pocket of Mcl-1 and inhibits HR activity. MI-223 has potent anti-tumor activity against lung cancer in vitro and in vivo. Olaparib is an FDA-approved PARP-1 inhibitor with anti-cancer efficacy; however, only patients with HR deficiency (e.g. BRCA1/2 mutations) respond to olaparib therapy. Since MI-223 inhibits HR-mediated DNA repair, this provides a rationale for combining MI-223 and olaparib to treat various cancers, including those without BRCA1/2 mutations. Combined treatment with MI-223 and olaparib synergistically suppresses lung cancer growth in vitro and in vivo. Since our data indicate that KRAS mutations can activate Mcl-1, we hypothesize that MI-223 alone or in combination with olaparib may be effective against lung cancers with KRAS mutations. MI-223-induced DSBs upregulate PD-L1 in tumor tissue from mutant KRAS driven lung cancer model, suggesting combination of MI- 223 with anti-PD-L1 may overcome PD-1 inhibitor resistance in KRAS-mutant lung cancer. To characterize and develop this novel Mcl-1 inhibitor MI-223 for the treatment of lung cancer, we propose two specific aims: (1) Determine whether and how KRAS mutations activate Mcl-1 leading to treatment resistance in human lung cancer cells. Studies will determine whether pMcl-1 at T163 is a novel prognostic biomarker and therapeutic target in patients with NSCLC; (2) Determine mechanism of action of novel Mcl-1 inhibitor MI-223 in killing human lung cancer cells. Studies will test the potency of MI-223 alone or in combination with PARP inhibitor olaparib in patient-derived lung cancer xenograft (PDX), radioresistant, and KRAS-mutant lung cancer xenografts. Determine whether MI-223 synergizes with olaparib or anti-PD-L1 to more effectively suppress tumor growth and prolong survival in genetically engineered mutant KRAS-driven lung cancer animal models. By targeting Mcl-1, we expect to develop a new class of anti-cancer agents and combination strategies for lung cancer treatment.

概括 KRAS突变激活Raf/MEK/ERK1/2，可以直接磷酸化Mcl-1的T163，从而增强Mcl-1的 KRAS 突变还会激活 PI3K/AKT，从而使 GSK-3 失活并抑制 GSK-3 介导的功能。我们捕获了 KRAS 突变激活的 ERK1/2 和 S159 处的 pMcl-1，以减少 Mcl-1 降解。 PI3K/AKT 途径通过 T163 处 pMcl-1 的上调和下调促进 Mcl-1 的稳定我们的初步数据显示肺癌组织中 T163 的 pMcl-1 增加。 NSCLC 患者，这与较差的生存结果相关，表明 T163 处的 pMcl-1 可能提供除了 Mcl-1 之外，我们还发现了 NSCLC 患者的新治疗靶点和预后生物标志物。典型的抗凋亡功能，在支持同源重组 (HR) 介导的过程中发挥着关键作用 DNA 双链断裂 (DSB) 的修复基于这一新功能，我们发现了一个全新的类别。小分子 Mcl-1 抑制剂 MI-223 与 Mcl-1 的 BH1 口袋相互作用并抑制 HR 活性。 MI-223 在体外和体内均具有有效的抗肺癌活性，Olaparib 是 FDA 批准的药物。 PARP-1抑制剂具有抗癌功效；但仅适用于HR缺陷（例如BRCA1/2突变）的患者由于 MI-223 抑制 HR 介导的 DNA 修复，这提供了一个理由。联合 MI-223 和奥拉帕尼治疗各种癌症，包括那些没有 BRCA1/2 突变的癌症。 MI-223 和奥拉帕尼联合治疗可在体外和体内协同抑制肺癌生长由于我们的数据表明 KRAS 突变可以激活 Mcl-1，因此我们单独或在体内捕获了 MI-223。与奥拉帕尼联合治疗可能有效对抗 MI-223 诱导的 DSB 突变肺癌。上调突变 KRAS 驱动的肺癌模型肿瘤组织中的 PD-L1，表明 MI- 223 与抗 PD-L1 可以克服 KRAS 突变肺癌中的 PD-1 抑制剂耐药性。开发这种新型 Mcl-1 抑制剂 MI-223 来治疗肺癌，我们提出了两个具体目标：（1）确定 KRAS 突变是否以及如何激活 Mcl-1 导致人肺治疗耐药研究将确定 T163 处的 pMcl-1 是否是一种新的预后生物标志物和治疗方法。 (2)确定新型Mcl-1抑制剂MI-223的杀伤作用机制研究将测试 MI-223 单独使用或与 PARP 抑制剂联合使用的功效。奥拉帕尼在患者来源的肺癌异种移植物 (PDX)、放射抗性和 KRAS 突变肺癌中的应用确定 MI-223 是否与奥拉帕尼或抗 PD-L1 协同作用以更有效地抑制基因工程突变 KRAS 驱动的肺癌动物模型中的肿瘤生长和延长生存期。通过针对 Mcl-1，我们期望开发一类新型抗癌药物和针对肺癌的联合策略癌症治疗。