Functional effects of all possible point mutations in oncogenes

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。

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.