Functional effects of all possible point mutations in oncogenes

描述（由申请人提供）：靶向抗癌治疗剂的有效性经常因获得耐药性而降低。对与癌基因功能相容的突变的全面理解应该定义可用于指导耐药的突变，并为合理开发具有降低耐药概率的改进的抑制剂提供指导。传统的功能分析方法 突变的影响依赖于随机产生的突变体，并且通常只能鉴定具有强烈选择表型的少数突变。我们提出了一种方法来系统地分析所有可能的单核苷酸取代的功能影响，在存在和不存在抑制剂的情况下，整个癌基因。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。只有与癌基因功能相容的突变才可用于耐药性演变。因此，识别功能突变的集合提供了一个强大的结构指导，可以在未来药物设计工作的早期阶段进行整合。

DESCRIPTION (provided by applicant): 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.