Project 3: Targeting Bax signaling to overcome treatment resistance in NSCLC

项目 3：靶向 Bax 信号传导以克服 NSCLC 的治疗耐药性

• 批准号: 10459442
• 负责人: Xingming Deng
• 金额: $ 36.47万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-10 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459442
• 关键词: Agonist; Animal Cancer Model; Antineoplastic Agents; Apoptosis; Apoptotic; Attenuated; Bax protein; Binding; Biological; C-terminal; Cancer Patient; Cell Death; Cells; Chemical Structure; Cisplatin; Development; Failure; Family member; Genetic Engineering; Homo; Human; In Vitro; Ionizing radiation; KRAS2 gene; KRASG12D; Lead; Link; Lung Neoplasms; MAPK3 gene; MEKs; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mitochondria; Modeling; Molecular Conformation; Mutation; Non-Small-Cell Lung Carcinoma; PDPK1 gene; PI3K/AKT; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Play; Prognostic Marker; Property; Protein Dephosphorylation; Proto-Oncogene Proteins c-akt; Radiation; Radiation therapy; Radio; Regimen; Reporting; Resistance; Role; Serine; Signal Transduction; Site; T-Lymphocyte; TP53 gene; Tail; Testing; Therapeutic Intervention; Treatment outcome; Tumor Tissue; Universities; Xenograft procedure; analog; anti-cancer; base; cancer therapy; cell killing; checkpoint inhibition; chemoradiation; chemotherapy; draining lymph node; lung cancer cell; mTOR Inhibitor; mTOR inhibition; member; mitochondrial membrane; mutant; novel; novel strategies; patient derived xenograft model; peripheral blood; predictive marker; programmed cell death protein 1; radiation resistance; radioresistant; small molecule; stem; therapeutic target; therapy resistant; tumor

Summary Bax functions as an essential gateway to apoptotic cell death. Targeting Bax provides a common pathway to treat NSCLC patients with KRAS or p53 mutations and to overcome resistance to radiotherapy and chemotherapy. We previously discovered that the serine (S)184 phosphorylation site of Bax is a critical switch to functionally control Bax’s proapoptotic activity. AKT and PKC have been identified as physiological Bax kinases that can directly phosphorylate Bax at the S184 site, leading to inactivation of its proapoptotic function. It is known that KRAS and p53 mutations can activate the PI3K/AKT survival pathway leading to increased resistance to radiotherapy or chemotherapy in various cancers, including lung cancer. Increased levels of phospho-Bax (pBax) were observed in tumor tissues in patients with non-small cell lung cancer (NSCLC). We hypothesize that pBax may serve as a new predictive and prognostic biomarker in NSCLC. Expression of KRAS G12D mutant or p53 R273H mutant or treatment with radiation, cisplatin or RAD001 resulted in activation of AKT and/or PKC leading to increased phosphorylation of Bax, which may contribute to radio-, chemo- or rapalog resistance. Development of small molecules that activate Bax may provide a novel approach for the treatment of mutant KRAS or mutant p53 lung cancer or for overcoming radio-, chemo- or rapalog resistance. We have identified a novel Bax activator, CYD-2-11, that selectively binds the S184 pocket of Bax protein but does not bind other Bcl2 family members. CYD-2-11 not only reverses radioresistance but also overcomes rapalog resistance in vitro. CYD-2-11 potently represses lung cancer xenografts by activating Bax and inducing apoptosis in tumor tissues. To characterize and develop this novel Bax activator for the treatment of resistant lung cancer, we propose two specific aims: (1) To determine whether and how KRAS and p53 mutations regulate Bax activity and treatment resistance in human lung cancer cells. Studies will determine whether pBax is a novel prognostic biomarker or therapeutic target in patients with NSCLC; (2) To develop novel small molecule Bax activator (CYD-2-11) by targeting the structural pocket around the Bax phosphorylation site for lung cancer therapy. Studies will test the antitumor efficacy of CYD-2-11 alone or in combination with ionizing radiation, chemotherapy, and/or mTOR inhibitor in patient-derived xenograft (PDX), radioresistant, and genetically engineered mutant KRAS-driven lung cancer animal models. By targeting Bax, we expect to develop a new class of anti-cancer agents and combination strategies for lung cancer treatment.

概括 Bax是凋亡细胞死亡的重要门户。靶向BAX提供了通往的通用途径 治疗NSCLC患者具有KRAS或p53突变的患者，并克服对放射疗法的抗药性和 化学疗法。我们以前发现丝氨酸184 BAX的磷酸化位点是关键开关 在功能上控制Bax的促凋亡活动。 AKT和PKC已被识别为物理Bax 可以直接在S184位点磷酸化BAX的激酶，从而导致其凋亡功能失活。 众所周知，KRAS和p53突变可以激活PI3K/AKT生存途径，从而增加 包括肺癌在内的各种癌症中对放疗或化学疗法的抗性。增加的水平 在非小细胞肺癌（NSCLC）患者中，在肿瘤组织中观察到磷酸bax（PBAX）。我们 假设PBAX可以作为NSCLC中的新预测和预后生物标志物。表达 KRAS G12D突变体或p53 R273H突变体或辐射处理，顺铂或Rad001导致 AKT和/或PKC的激活导致BAX的磷酸化增加，这可能有助于无线电， 化学抗性或抗乳链酰基的耐药性。激活Bax的小分子的开发可能会提供新颖的 处理突变KRAS或突变体p53肺癌或克服无线电，化学或化学或 Rapalog抗性。我们已经确定了一种新型的Bax激活剂CYD-2-11，该激活剂有选择地结合S184袋 Bax蛋白质的，但不结合其他Bcl2家族成员。 CYD-2-11不仅逆转放射线，而且还可以 还可以在体外克服Rapalog耐药性。 CYD-2-11可能通过激活反映肺癌的Xenographictic Bax并诱导肿瘤组织凋亡。表征和开发这种新颖的Bax激活剂 抗性肺癌的治疗，我们提出了两个具体目的：（1）确定KRAS是否以及如何 和p53突变调节人类肺癌细胞中的BAX活性和耐药性。研究将 确定PBAX是NSCLC患者的新型预后生物标志物还是治疗靶标的； （2）至 通过靶向Bax周围的结构袋来开发新型的小分子Bax激活剂（CYD-2-11） 肺癌治疗的磷酸化位点。研究将单独或在CYD-2-11的抗肿瘤效率或中 在患者衍生异种移植物（PDX）中，与电离辐射，化学疗法和/或MTOR抑制剂结合使用， 辐射耐药物和基因工程突变体KRAS驱动的肺癌动物模型。通过靶向bax， 我们希望开发一种新的抗癌药和肺癌治疗的组合策略。