The Role of Protein Kinases in NRF2-driven Lung Squamous Cell Carcinoma

蛋白激酶在 NRF2 驱动的肺鳞状细胞癌中的作用

• 批准号: 10296668
• 负责人: Michael Benjamin Major
• 金额: $ 49.37万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10296668
• 关键词: 3-Dimensional; Air; Animals; Antioxidants; Apoptosis; Biology; CUL3 gene; Cancer Biology; Cancer Model; Cancer Patient; Cancer cell line; Cell Culture Techniques; Cell Differentiation process; Cell Line; Cell model; Cellular biology; Chemicals; Clinical; Communication; Cytotoxic Chemotherapy; Cytotoxic agent; DNA sequencing; Data; Development; Disease model; Epithelial Cells; Equilibrium; Evaluation; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Screening; Genetic Transcription; Genetically Engineered Mouse; Genotype; Goals; Growth; H1299; Head and Neck Cancer; Human; Hypermethylation; In Vitro; Intervention; Lead; Liquid substance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of urinary bladder; Modeling; Molecular; Mus; Mutation; NF-E2-related factor 2; Oncogenes; Outcome; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Pharmacology; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Pilot Projects; Positioning Attribute; Pre-Clinical Model; Prognosis; Protein Kinase; Protein Overexpression; Proteins; Proteomics; Radiation; Reactive Oxygen Species; Regulation; Research; Research Personnel; Resources; Role; Sampling; Signal Pathway; Signal Transduction; Site; Squamous Cell Lung Carcinoma; Stress; Supervision; System; TP53 gene; Testing; Therapeutic; Therapeutic Index; Therapeutic Intervention; Tissues; Tumor-infiltrating immune cells; Validation; Work; Xenobiotics; bronchial epithelium; cancer cell; chemotherapy; effective therapy; experience; experimental study; genetic signature; genome sequencing; in vivo Model; innovation; insight; loss of function; lung cancer cell; misfolded protein; mouse model; multidisciplinary; new therapeutic target; novel; overexpression; patient prognosis; phosphoproteomics; programs; promoter; protein expression; protein kinase inhibitor; response; small molecule; success; systemic toxicity; targeted treatment; therapeutic target; therapy development; therapy resistant; tool; transcription factor; tumor; tumor metabolism; tumor progression; two-dimensional

Project Summary Despite the dismal prognosis for patients with advanced lung squamous cell cancer (LUSC), few effective treatments of only limited benefit exist. Cytotoxic therapy with radiation remains the mainstay for most patients. However, it carries a relatively narrow therapeutic index and patients invariably suffer treatment-related systemic toxicities. The development of new targeted therapies for LUSC remains a high priority. One of the most significant discoveries from lung cancer genome sequencing is the frequent (~30%) alterations of the KEAP1- NRF2 signaling pathway. The NRF2 antioxidant signaling pathway constitutes the primary cellular defense system against oxidative stress. Several mechanisms responsible for governing NRF2 activity are known, however they have proven largely intractable for therapeutic intervention (eg. transcription factors). Recent studies have revealed that several protein kinases functionally impact NRF2, although a global evaluation of how the kinome instructs NRF2 biology remains untested. Being among the most druggable of protein classes, kinases and phosphatases offer attractive targets for NRF2-directed treatment intervention. Our preliminary data have established reciprocal communication between NRF2 and protein kinases, including upstream modifiers and downstream effectors. Therefore, we hypothesize that the kinome encompasses key regulators of NRF2 signaling and holds novel therapeutic targets for NRF2-active lung cancer. We have assembled a unique multidisciplinary team of investigators with experience in LUSC molecular signaling, cancer cell biology, animal and cell culture models, proteomics, and clinical therapeutics to decipher the interactions between the kinome and NRF2 signaling, identify novel therapeutic targets and analyze them in pre-clinical models. Our specific aims include: (1) IDENTIFY KINASES THAT REGULATE NRF2; (2) IDENTIFY NRF2-RESPONSIVE KINASES AND PHOSPHATASES; and (3) EVALUATE KINOME FUNCTION IN NOVEL MODELS OF NRF2 ACTIVE LUSC. This project shows strong innovation through kinome proteomic profiling of LUSC tumor samples and cell lines, high-throughput chemical screens, gain- and loss-of-function genetic screens, and the application of unique 2- and 3-dimensional cell culture models. Our experiments employ gene targeted-transformation of human bronchial epithelial cells and novel genetically engineered mouse models and derived cell lines. The results of this work will reveal protein kinases that functionally impact NRF2 biology, and in doing so may lead to new effective treatments for LUSC and other NRF2-active tumors, including head and neck cancer, bladder cancer, and ovarian cancer. Ultimately, the successful completion of our proposed studies will provide a roadmap for similar efforts on targeted therapeutic discovery in these other human malignancies.

项目总结

项目成果

Correlation of alterations in the KEAP1/CUL3/NFE2L2 pathway with radiation failure in larynx squamous cell carcinoma.

• DOI: 10.1002/lio2.588
• 发表时间: 2021-08
• 期刊: Laryngoscope investigative otolaryngology
• 影响因子: 1.9
• 作者: Sheth S;Farquhar DR;Schrank TP;Stepp W;Mazul A;Hayward M;Lenze N;Little P;Jo H;Major MB;Chera BS;Zevallos JP;Hayes DN
• 通讯作者: Hayes DN

TP53, CDKN2A/P16, and NFE2L2/NRF2 regulate the incidence of pure- and combined-small cell lung cancer in mice.

• DOI: 10.1038/s41388-022-02348-0
• 发表时间: 2022-06
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Hamad, Samera H.;Montgomery, Stephanie A.;Simon, Jeremy M.;Bowman, Brittany M.;Spainhower, Kyle B.;Murphy, Ryan M.;Knudsen, Erik S.;Fenton, Suzanne E.;Randell, Scott H.;Holt, Jeremiah R.;Hayes, D. Neil;Witkiewicz, Agnieszka K.;Oliver, Trudy G.;Ben Major, M.;Weissman, Bernard E.
• 通讯作者: Weissman, Bernard E.

PKIS deep dive yields a chemical starting point for dark kinases and a cell active BRSK2 inhibitor.

• DOI: 10.1038/s41598-020-72869-9
• 发表时间: 2020-09-28
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Tamir TY;Drewry DH;Wells C;Major MB;Axtman AD
• 通讯作者: Axtman AD

The Cancer/Testes (CT) Antigen HORMAD1 promotes Homologous Recombinational DNA Repair and Radioresistance in Lung adenocarcinoma cells.

癌症/睾丸（CT）抗原Hormad1促进肺腺癌细胞中的同源重组DNA修复和放射线。

• DOI: 10.1038/s41598-018-33601-w
• 发表时间: 2018-10-17
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Gao Y;Kardos J;Yang Y;Tamir TY;Mutter-Rottmayer E;Weissman B;Major MB;Kim WY;Vaziri C
• 通讯作者: Vaziri C

Loss of SWI/SNF Chromatin Remodeling Alters NRF2 Signaling in Non-Small Cell Lung Carcinoma.

• DOI: 10.1158/1541-7786.mcr-20-0082
• 发表时间: 2020-12
• 期刊: Molecular cancer research : MCR
• 作者: Song S;Nguyen V;Schrank T;Mulvaney K;Walter V;Wei D;Orvis T;Desai N;Zhang J;Hayes DN;Zheng Y;Major MB;Weissman BE
• 通讯作者: Weissman BE