肿瘤抑制因子p53在癌症中被数千种不同的杂合突变体失活，但它们的个体药物敏感性仍然很难确定。在本研究中，我们评估了800个常见的p53突变体在穷举代表性复合救援剂三氧化二砷（ATO）的转录活性、细胞生长抑制和小鼠抑制肿瘤活性方面的复苏效力。复苏效力主要由变异残基的溶剂可接近性确定，这是决定突变体是结构类突变还是临床类突变的关键因素，和温度敏感性，这是突变体蛋白是否能在低温下重新组装为野生型DNA结合表面的能力。总共有390个p53突变体得到了不同程度的救助，因此被称为1型、2a型和2b型突变体，具体取决于它们被救助的程度。其中33种1型突变体的救助程度与野生型相当。在人类肿瘤异种移植模型小鼠试验中，ATO优先抑制携带1型和2a型突变体的肿瘤的生长。在ATO临床试验中，我们报告了首个携带1型V272M突变体的患者中p53突变体的再激活。在10种癌症的47个细胞系中，ATO优先且有效地救助1型和2a型突变体，支持ATO在救助突变型p53中的广泛适用性。我们的研究为科学和临床社区提供了众多p53突变体的药物敏感性资源（www.rescuep53.net），并提出了一种基于个体突变体等位基因而不是突变类型的概念性p53靶向策略。

Tumor suppressor p53 is inactivated by thousands of heterogeneous mutations in cancer, but their individual druggability remains largely elusive. Here, we evaluated 800 common p53 mutants for their rescue potencies by the representative generic rescue compound arsenic trioxide (ATO) in terms of transactivation activity, cell growth inhibition, and mouse tumor-suppressive activities. The rescue potencies were mainly determined by the solvent accessibility of the mutated residue, a key factor determining whether a mutation is a structural one, and the temperature sensitivity, the ability to reassemble the wild-type DNA binding surface at a low temperature, of the mutant protein. A total of 390 p53 mutants were rescued to varying degrees and thus were termed as type 1, type 2a, and type 2b mutations, depending on the degree to which they were rescued. The 33 type 1 mutations were rescued to amounts comparable to the wild type. In PDX mouse trials, ATO preferentially inhibited growth of tumors harboring type 1 and type 2a mutants. In an ATO clinical trial, we report the first-in-human mutant p53 reactivation in a patient harboring the type 1 V272M mutant. In 47 cell lines derived from 10 cancer types, ATO preferentially and effectively rescued type 1 and type 2a mutants, supporting the broad applicability of ATO in rescuing mutant p53. Our study provides the scientific and clinical communities with a resource of the druggabilities of numerous p53 mutations (www.rescuep53.net) and proposes a conceptual p53-targeting strategy based on individual mutant alleles rather than mutation type.