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

基本信息

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
项目类别：
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

项目摘要

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 是细胞凋亡的重要途径，靶向 Bax 提供了一条常见的途径。治疗携带 KRAS 或 p53 突变的 NSCLC 患者并克服对放疗的耐药性我们之前发现 Bax 的丝氨酸 (S)184 磷酸化位点是一个关键开关。功能性控制 Bax 的促凋亡活性的 AKT 和 PKC 已被确定为生理性 Bax。激酶可直接在 S184 位点磷酸化 Bax，导致其促凋亡功能失活。众所周知，KRAS 和 p53 突变可以激活 PI3K/AKT 存活途径，从而导致各种癌症（包括肺癌）对放疗或化疗的耐药性增加。在非小细胞肺癌 (NSCLC) 患者的肿瘤组织中观察到磷酸化 Bax (pBax)。 pBax 可能作为 NSCLC 表达的新预测和预后生物标志物。 KRAS G12D 突变体或 p53 R273H 突变体或放射治疗、顺铂或 RAD001 导致 AKT 和/或 PKC 的激活导致 Bax 磷酸化增加，这可能有助于放射、开发激活 Bax 的小分子可能会提供一种新的耐药性。用于治疗突变 KRAS 或突变 p53 肺癌或克服放射、化学或我们发现了一种新型 Bax 激活剂 CYD-2-11，它选择性地结合 S184 口袋。 Bax 蛋白但不结合其他 Bcl2 家族成员，不仅可以逆转放射抗性，而且可以逆转放射抗性。还克服了体外 rapalog 耐药性，通过激活 CYD-2-11 有效抑制肺癌异种移植物。 Bax 并诱导肿瘤组织细胞凋亡表征和开发这种新型 Bax 激活剂。对于耐药性肺癌的治疗，我们提出了两个具体目标：（1）确定 KRAS 是否以及如何 p53 突变调节人类肺癌细胞中的 Bax 活性和治疗耐药性。确定 pBax 是否是 NSCLC 患者的新型预后生物标志物或治疗靶点 (2) 通过靶向 Bax 周围的结构袋开发新型小分子 Bax 激活剂 (CYD-2-11) 肺癌治疗的磷酸化位点研究将测试 CYD-2-11 单独或联合使用的抗肿瘤功效。与电离辐射、化疗和/或 mTOR 抑制剂联合用于患者来源的异种移植物 (PDX)，抗辐射和基因工程突变 KRAS 驱动的肺癌动物模型我们期望开发一类新型抗癌药物和治疗肺癌的联合策略。