Protein Arginine Methylation in Chemotherapy Resistance

化疗耐药中的蛋白质精氨酸甲基化

基本信息

批准号：
9242960
负责人：
Wei Xu
金额：
$ 16万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9242960
关键词：
Address Adjuvant Aging Anthracyclines Antineoplastic Agents Arginine BRAF gene Biological Assay Biological Markers Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Breast Cancer therapy Cancer Patient Categories Cell Culture Techniques Cell Line Cells ChIP-seq Clinical Clinical Management Colon Carcinoma Cytotoxic agent DNA Damage Databases Development Down-Regulation Drug Combinations Drug Controls Drug resistance Drug toxicity Fluorouracil Freezing Gene Targeting Genes Genetic Transcription Goals Histone H3 Human Implant In Vitro Individual Knock-in Knock-out Link Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of lung Mammary Neoplasms Maps Mass Spectrum Analysis Mediating Mediator of activation protein Methylation Methyltransferase Mitosis Modeling Multi-Drug Resistance Mutate Mutation Neoplasm Metastasis Oncologist Operative Surgical Procedures Pathologic Patients Pharmaceutical Preparations Prediction of Response to Therapy Proteins RNA Polymerase II Recurrence Reporting Research Resistance Resistance development Risk Signal Transduction Site Specimen Staining method Stains Testing The Cancer Genome Atlas Therapeutic Intervention Tissue Microarray Transforming Growth Factors United States Up-Regulation Woman Xenograft Model Xenograft procedure cancer diagnosis cancer therapy chemotherapy clinically relevant coactivator-associated arginine methyltransferase 1 cohort drug development drug sensitivity exome sequencing in vivo inhibitor/antagonist knock-down lung Carcinoma malignant breast neoplasm melanoma mortality mouse model mutant new therapeutic target novel oncoprotein p21 outcome forecast overexpression personalized approach polyclonal antibody predicting response prevent receptor resistance mechanism response taxane triple-negative invasive breast carcinoma tumor tumor progression tumor xenograft zinc finger nuclease

项目摘要

PROJECT SUMMARY Chemotherapy continues to be an important component of therapy for breast cancer, given to reduce the risk of metastatic recurrence. Although response (sensitivity) or lack of response (resistance) to chemotherapy is associated with prognosis, there is currently no validated commercial assay available which specifically predicts response to chemotherapy. Personalized approaches to cancer therapy are needed to select a drug or combination of drugs to which a tumor is most sensitive, and to avoid the toxicity of drugs to which the tumor is or becomes resistant. Such biomarker will assist oncologists in the daily clinical management of aging patients who are fragile to multiple chemotherapies and triple negative breast cancer patients whose major treatment option is chemotherapy. Coactivator associated arginine methyltransferase 1 (CARM1) is a protein arginine (R) methyltransferase which can methylate histone H3 and a variety of non-histone substrates. We recently identified a mediator of RNA polymerase II transcription subunit 12 (MED12) as a novel substrate for CARM1. The proposed project will determine whether methylation of MED12 is a predictor for chemo-sensitivity in breast cancer. We have mapped the methylation sites of MED12 to R1862 and R1912. Coincidently, mutations on R1862 had been reported in lung and cervical cancers, and mutations on R1912 had been found in a melanoma patient who developed resistance to BRAF inhibitor. We found that overexpression of MED12 wild-type, but not MED12R1862K,R1912K mutant, increased sensitivity of HEK293 cells to 5-FU and anthracyclines. Interestingly, the MED12 methylation dependent mechanism is distinct from activation of TGF-βR signaling as reported for complete knockout of MED12 in lung and colon cancers. Further, we have identified targets regulated by methylated MED12 that may determine chemo-sensitivity. We hypothesize that methylation of MED12 by CARM1 represents an important mechanism conferring chemosensitivity. The proposed research will directly address (1) whether MED12 methylation predicts sensitivity of breast cancer cells to commonly used chemotherapies in cell culture and xenograft tumor models; (2) define the mechanism of methylated-MED12 controlled chemosensitivity; and (3) test the clinical relevance of the MED12 methylation in chemo- resistance using large cohorts of clinical specimens. The goal is to delineate the methylation dependent mechanism for chemotherapy resistance and uncover new targets for therapeutic intervention.

项目概要化疗仍然是乳腺癌治疗的重要组成部分，旨在减少尽管有反应（敏感性）或缺乏反应（耐药性）。化疗与预后相关，目前尚无经过验证的商业化验方法它专门预测了癌症治疗的个性化方法。需要选择肿瘤最敏感的药物或药物组合，并避免毒性肿瘤对其具有或变得具有抗药性的药物的这些生物标志物将有助于肿瘤学家的日常工作。对多种化疗和三阴性乳腺癌脆弱的老年患者的临床管理主要治疗选择是化疗的癌症患者。辅激活剂相关精氨酸甲基转移酶 1 (CARM1) 是一种蛋白质精氨酸 (R) 甲基转移酶它可以甲基化组蛋白 H3 和多种非组蛋白底物我们最近发现了一种介质。 RNA 聚合酶 II 转录亚基 12 (MED12) 作为 CARM1 的新型底物。该项目将确定 MED12 的甲基化是否是乳腺癌化疗敏感性的预测因子。我们已经将 MED12 的甲基化位点映射到 R1862 和 R1912，巧合的是，R1862 上的突变。已在肺癌和宫颈癌中报告过，并且在黑色素瘤中发现了 R1912 突变我们发现 MED12 野生型过度表达，但对 BRAF 抑制剂产生耐药性。不是MED12R1862K、R1912K突变体，HEK293细胞对5-FU和蒽环类药物的敏感性增加。提示，MED12 甲基化依赖性机制与 TGF-βR 信号传导的激活不同据报道，在肺癌和结肠癌中完全敲除 MED12，此外，我们还确定了靶标。受甲基化 MED12 调节，可能决定化疗敏感性。 CARM1 的 MED12 代表了赋予化学敏感性的重要机制。研究将直接解决 (1) MED12 甲基化是否预测乳腺癌细胞对细胞培养和异种移植肿瘤模型中常用的化疗方法；（2）明确其机制；甲基化 MED12 控制的化学敏感性；以及 (3) 测试 MED12 甲基化的临床相关性使用大量临床样本来研究化疗耐药性，目标是描绘甲基化。化疗耐药的依赖机制并揭示治疗干预的新靶点。