Roles of TP53 gene in the development of resistance to PI3K inhibitor resistances in CRISPR-Cas9-edited lung adenocarcin
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ORIGINAL ARTICLE
Roles of TP53 gene in the development of resistance to PI3K inhibitor resistances in CRISPR-Cas9-edited lung adenocarcinoma cells Jiayun Hou & Xin Cao Xiangdong Wang
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Yunfeng Cheng
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Received: 31 January 2020 / Accepted: 19 March 2020 # Springer Nature B.V. 2020
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-nonrelated 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 Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10565-020-09523-7) contains supplementary material, which is available to authorized users. J. Hou : X. Cao (*) : Y. Cheng : X. Wang Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical School, Shanghai, China e-mail: [email protected]
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. Keywords TP53 mutation . Drug resistance . CRISPRCas9 . PI3K inhibitor . Cancer treatment
Introduction
: X. Wang
Y. Cheng Jinshan Hospital Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University Shanghai Medical School, Shanghai, China Y. Cheng : X. Wang Shanghai Engineering Research Center of AI-Technology for Cardiopulmonary Diseases, Shanghai, China Y. Cheng (*) : X. Wang (*) Shanghai Institute of Clinical Bioinformatics, Shanghai, China e-mail: [email protected] e-mail: [email protected]
Lung adenocarcinoma is one of the most common types of lung cancer, accounting for about 40% death of patients with lung cancers. Therapeutic options for lung adenocarcinoma vary among patient conditions and needs, and targeted therapy and chemotherapy are main choices (Cancer Genome Atlas Research Network 2014; Zagryazhskaya et al. 2015). However, the efficiencies of targeted therapies as well as the chemotherapies towards lung adenocarcinoma are usually hindered b
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