The mutation rates of tumor suppressor protein p53 gene (TP53) are high in lung adenocarcinoma and promote the development of acquired drug resistance. The present study evaluated the p53-dependent role in lung cancer cell sensitivity to PI3K-specific inhibitors, PI3K-associated inhibitors, PI3K-non-related inhibitors, and protein-based stimuli using designed p53 mutation. We found that the deletion of p53 key regions from amino acid 96 to 393 with the CRISPR-Cas9 altered multi-dimensional structure and sequencing of p53, probably leading the secondary changes in chemical structures and properties of PI3K subunit proteins or in interactions between p53 and PI3K isoform genes. The p53-dependent cell sensitivity varied among target specificities, drug chemical properties, mechanism-specific signal pathways, and drug efficacies, independently upon the size of molecules. The effects of the designed p53 mutation highly depend upon p53-involved molecular mechanisms in the cell. Our results indicate that lung cancer cell resistance to drug can develop with dynamic formations of p53 mutations changing the cell sensitivity. This may explain the real-time occurrence of cancer cell resistance to drug treatment, during which drugs may induce the new mutations of p53. Thus, it is important to dynamically monitor the formation of new mutations during the therapy and discover new drug resistance–specific targets.

抑癌蛋白p53基因（TP53) 在肺腺癌中含量高并促进获得性耐药性的发展。本研究使用设计的 p53 突变评估了 p53 依赖性在肺癌细胞对 PI3K 特异性抑制剂、PI3K 相关抑制剂、PI3K 非相关抑制剂和基于蛋白质的刺激物的敏感性中的作用。我们发现用 CRISPR-Cas9 从 96 到 393 位氨基酸缺失 p53 关键区域改变了 p53 的多维结构和测序，可能导致 PI3K 亚基蛋白的化学结构和性质或 p53 和 p53 之间相互作用的二次变化。 PI3K 同种型基因。p53 依赖性细胞敏感性在靶点特异性、药物化学性质、机制特异性信号通路和药物功效之间变化，独立于分子大小。设计的 p53 突变的影响高度依赖于细胞中 p53 参与的分子机制。我们的结果表明肺癌细胞对药物的耐药性可以随着 p53 突变的动态形成改变细胞敏感性而发展。这或许可以解释癌细胞对药物治疗的耐药性的实时发生，在此期间药物可能会诱发p53的新突变。因此，重要的是在治疗过程中动态监测新突变的形成并发现新的耐药特异性靶点。在此期间，药物可能会诱发 p53 的新突变。因此，重要的是在治疗过程中动态监测新突变的形成并发现新的耐药特异性靶点。在此期间，药物可能会诱发 p53 的新突变。因此，重要的是在治疗过程中动态监测新突变的形成并发现新的耐药特异性靶点。