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Functional effects of all possible point mutations in oncogenes

癌基因中所有可能的点突变的功能影响

基本信息

批准号：
8638362
负责人：
DANIEL N BOLON
金额：
$ 20.33万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8638362
关键词：
17-(Allylamino)-17-demethoxygeldanamycin Accounting Address Amino Acids Antineoplastic Agents BRAF gene Binding Biological Models Cell Culture Techniques Cells Clinical Dasatinib Development Drug Design Drug resistance Effectiveness Escape Mutant Evolution Follow-Up Studies Fostering Foundations Future Genes Growth Health Human Imatinib Individual Interleukin-3 Knowledge Libraries Location Malignant Neoplasms Mammalian Cell Maps Mediating Modeling Molecular Chaperones Monitor Mutagenesis Mutation Nucleotides Oncogenes Patients Pharmaceutical Preparations Phenotype Phosphotransferases Point Mutation Polymerase Probability Publishing Refractory Relative (related person)Resistance Route Sampling Staging Testing Therapeutic Yeasts anti-cancer therapeutic base bcr-abl Fusion Proteins cancer cell cancer therapy cell growth clinically relevant deep sequencing design fitness improved inhibitor/antagonist killings multicatalytic endopeptidase complex mutant new technology novel strategies pressure prevent public health relevance research study resistance mutation

项目摘要

The effectiveness of targeted anti-cancer therapeutics is frequently reduced by the acquisition of drug- resistance. A comprehensive understanding of the mutations compatible with oncogene function should define the mutations available to direct drug-resistance and provide a guide for the rational development of improved inhibitors with reduced probability of resistance. Traditional approaches to analyze the functional effects of mutations rely on randomly generated mutants and typically can only identify a handful of mutations with a strongly selected phenotype. We propose an approach to systematically analyze the functional effects of all possible single-nucleotide substitutions for entire oncogenes both in the presence and absence of inhibitors. Our approach will systematically define the positive or negative impact of each mutation on cell growth. Only mutations that are compatible with oncogene function should be available to drug resistance evolution. Therefore, identifying the set of functional mutations provides a powerful structural guide that can be incorporated in the early stages of future drug design efforts.

靶向抗癌疗法的有效性经常因获得药物而降低- 抵抗。对与癌基因功能相容的突变的全面理解应该定义该突变可直接指导耐药，为合理发展改良提供指导抗药性降低的抑制剂。传统的方法来分析功能效应突变依赖于随机产生的突变，通常只能识别少数带有强选择表型。我们提出了一种方法来系统地分析所有在存在和不存在抑制物的情况下，对整个癌基因进行可能的单核苷酸替换。我们的方法将系统地定义每个突变对细胞生长的积极或消极影响。仅限与癌基因功能相容的突变应可用于耐药进化。因此，确定一组功能突变提供了一个强大的结构指南，可以纳入未来药物设计工作的早期阶段。