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Roles of TP53 gene in the development of resistance to PI3K inhibitor resistances in CRISPR-Cas9-edited lung adenocarcinoma cells

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Abstract

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.

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Funding

The work was supported by Operation funding of Shanghai Institute of Clinical Bioinformatics and Shanghai Engineering and Technology Center for Artificial Intelligence of Lung and Heart Diseases from Zhongshan Hospital, the National Nature Science Foundation of China (81873409), and National Key Research and Development Program of Precision Medicine (2017YFC0909500).

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Authors and Affiliations

  1. Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical School, Shanghai, China

    Jiayun Hou, Xin Cao, Yunfeng Cheng & Xiangdong Wang

  2. Jinshan Hospital Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University Shanghai Medical School, Shanghai, China

    Yunfeng Cheng & Xiangdong Wang

  3. Shanghai Engineering Research Center of AI-Technology for Cardiopulmonary Diseases, Shanghai, China

    Yunfeng Cheng & Xiangdong Wang

  4. Shanghai Institute of Clinical Bioinformatics, Shanghai, China

    Yunfeng Cheng & Xiangdong Wang

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  1. Jiayun Hou
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  2. Xin Cao
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  3. Yunfeng Cheng
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  4. Xiangdong Wang
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Correspondence to Xin Cao, Yunfeng Cheng or Xiangdong Wang.

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Hou, J., Cao, X., Cheng, Y. et al. Roles of TP53 gene in the development of resistance to PI3K inhibitor resistances in CRISPR-Cas9-edited lung adenocarcinoma cells. Cell Biol Toxicol 36, 481–492 (2020). https://doi.org/10.1007/s10565-020-09523-7

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