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，可以在T163处直接磷酸化Mcl-1，从而增强MCL-1 功能。 KRAS突变还激活PI3K/AKT，可以使GSK-3失活并抑制GSK-3介导 S159的PMCL-1可减少MCL-1降解。我们假设KRAS突变激活ERK1/2和 PI3K/AKT途径通过在T163处上调和下调有助于MCL-1的稳定在肺癌中S159的PMCL-1。我们的初步数据表明，在T163中，肿瘤组织中T163的PMCL-1增加了 NSCLC患者与生存率较差有关，表明T163的PMCL-1可能会提供 NSCLC患者的新治疗靶标和预后生物标志物。我们发现MCL-1除了它规范的抗凋亡功能，在支持同源重组（HR）介导的方面起着至关重要的作用 DNA双链断裂（DSB）的修复。基于这个新颖的功能，我们发现了一个全新的班级小分子Mcl-1抑制剂MI-223与MCL-1的BH1袋相互作用并抑制HR活性。 MI-223在体外和体内具有针对肺癌的潜在抗肿瘤活性。 Olaparib是FDA批准的 PARP-1抑制剂具有抗癌效率；但是，只有人力资源缺乏症患者（例如BRCA1/2突变）对Olaparib疗法做出反应。由于MI-223抑制了HR介导的DNA修复，因此为组合MI-223和Olaparib以治疗各种癌症，包括没有BRCA1/2突变的癌症。与MI-223和Olaparib结合治疗协同抑制了体外和IN的肺癌生长体内。由于我们的数据表明KRAS突变可以激活Mcl-1，因此我们假设单独或单独或IN中的MI-223 与Olaparib结合使用KRAS突变的肺癌可能有效。 MI-223诱导的DSB 从突变kras驱动肺癌模型中上调肿瘤组织中的PD-L1，这表明MI- 223具有抗PD-L1的223可以克服KRAS突变肺癌中的PD-1抑制剂耐药性。表征和开发这种新型的Mcl-1抑制剂MI-223用于治疗肺癌，我们提出了两个具体目的：（1）确定KRAS突变是否以及如何激活MCL-1导致人肺的治疗耐药性癌细胞。研究将确定T163处的PMCL-1是否是一种新型的预后生物标志物和治疗 NSCLC患者的目标；（2）确定新型MCL-1抑制剂MI-223在杀死中的作用机理人肺癌细胞。研究将单独测试MI-223或与PARP抑制剂的效力 Olaparib在患者来源的肺癌异种移植（PDX），放射性抗药性和KRAS突变肺癌中异种移植物。确定MI-223是否与Olaparib或抗PD-L1合成以更有效地抑制肿瘤的生长和延长的一般工程突变体KRAS驱动的肺癌动物模型的生存。通过针对MCL-1，我们希望开发新的抗癌剂和肺部组合策略癌症治疗。