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: 10210202
• 负责人: Xingming Deng
• 金额: $ 33.89万
• 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/10210202
• 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; Structure; 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.

摘要 BAX是细胞凋亡的重要通道。以BAX为目标提供了一条共同的途径 治疗带有KRAS或P53突变的非小细胞肺癌患者，并克服对放射治疗和 化疗。我们先前发现Bax的丝氨酸(S)184磷酸化位点是一个关键的开关 从功能上控制Bax的促凋亡活性。Akt和PKC已被鉴定为生理性bax 可以直接在S184位点磷酸化Bax的激酶，导致其促凋亡功能失活。 已知KRAS和P53突变可以激活PI3K/AKT生存通路，导致 包括肺癌在内的各种癌症对放射治疗或化疗的抵抗。增加了 观察了非小细胞肺癌(NSCLC)患者肿瘤组织中磷酸化Bax(PBax)的表达。我们 假设pBax可作为一种新的预测和预测NSCLC预后的生物标志物。的表达 KRAS G12D突变或p53 R273H突变或放射治疗、顺铂或RAD001导致 Akt和/或PKC的激活导致bax的磷酸化增加，这可能有助于放射性- 对化疗或雷帕洛格耐药。开发激活Bax的小分子可能会提供一种新的 治疗突变型KRAS或突变型p53肺癌或克服放疗、化疗或化疗的方法 对拉帕洛格耐药。我们已经确定了一种新型的Bax激活剂，CyD-2-11，它可以选择性地结合S184口袋 Bax蛋白的结合，但不结合其他Bcl2家族成员。CyD-2-11不仅逆转辐射抗性，而且 也克服了体外对雷帕洛尔的耐药性。Cyd-2-11激活抑制肺癌移植瘤的实验研究 Bax和诱导肿瘤组织中的细胞凋亡。为了表征和开发这种新型的Bax激活剂 对于耐药肺癌的治疗，我们提出了两个具体的目标：(1)确定KRAS是否和如何 而p53突变调节人肺癌细胞中Bax的活性和治疗耐药性。研究将会 确定pBax是否是非小细胞肺癌患者新的预后生物标志物或治疗靶点；(2) 通过靶向Bax周围的结构口袋开发新型小分子Bax激活剂(CyD-2-11) 肺癌治疗中的磷酸化位点。研究将测试CyD-2-11单独或联合应用的抗肿瘤效果 与电离辐射、化疗和/或mTOR抑制剂联合应用于患者来源的异种移植(PDX)， 抗辐射和基因工程突变的KRAS驱动的肺癌动物模型。通过瞄准Bax， 我们希望开发一类新的抗癌药物和肺癌治疗的联合策略。