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Contribution of p53 in sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer

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Abstract
The emergence of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) with activating EGFR mutations is a major hindrance to treatment. We investigated the effects of p53 in primary sensitivity and acquired resistance to EGFR-TKIs in NSCLC cells. Changes in sensitivity to EGFR-TKIs were determined using p53 overexpression or knockdown in cells with activating EGFR mutations. We investigated EMT-related molecules, morphologic changes, and AXL induction to elucidate mechanisms of acquired resistance to EGFR-TKIs according to p53 status. Changes in p53 status affected primary sensitivity as well as acquired resistance to EGFR-TKIs according to cell type. Firstly, p53 silencing did not affect primary and acquired resistance to EGFR-TKIs in PC-9 cells, but it led to primary resistance to EGFR-TKIs through AXL induction in HCC827 cells. Secondly, p53 silencing in H1975 cells enhanced the sensitivity to osimertinib through the emergence of mesenchymal-to-epithelial transition, and the emergence of acquired resistance to osimertinib in p53 knockout cells was much slower than in H1975 cells. Furthermore, two cell lines (H1975 and H1975/p53(KO)) demonstrated the different mechanisms of acquired resistance to osimertinib. Lastly, the introduction of mutant p53-R273H induced the epithelial-to-mesenchymal transition and exerted resistance to EGFR-TKIs in cells with activating EGFR mutations. These findings indicate that p53 mutations can be associated with primary or acquired resistance to EGFR-TKIs. Thus, the status or mutations of p53 may be considered as routes to improving the therapeutic effects of EGFR-TKIs in NSCLC.
Author(s)
노진경이재철최창민Dong Ha KimHyeonjeong LeeHyojeong ParkSangyong JungSeon Ye KimYoung Hoon SungYun Jung Choi
Issued Date
2021
Type
Article
Keyword
Acrylamides - pharmacologyAniline Compounds - pharmacologyAnimalsAxl proteinBiomarkersTumorCarcinomaNon-Small-Cell Lung - drug therapyCarcinomaNon-Small-Cell Lung - geneticsCarcinomaNon-Small-Cell Lung - metabolismCarcinomaNon-Small-Cell Lung - pathologyCell LineTumorDisease ModelsAnimalDose-Response RelationshipDrugDrug ResistanceNeoplasm - geneticsEpidermal growth factorEpidermal growth factor receptorsEpithelial-Mesenchymal Transition - drug effectsEpithelial-Mesenchymal Transition - geneticsErbB Receptors - antagonists & inhibitorsHumansLung cancerLung Neoplasms - drug therapyLung Neoplasms - geneticsLung Neoplasms - metabolismLung Neoplasms - pathologyMesenchymeMolecular Targeted TherapyMutationNon-small cell lung carcinomaProtein Kinase Inhibitors - pharmacologyProtein Kinase Inhibitors - therapeutic useProtein-tyrosine kinaseSmall cell lung carcinomaTumor Suppressor Protein p53 - geneticsTumor Suppressor Protein p53 - metabolismTyrosine
DOI
10.1038/s41598-021-99267-z
URI
https://oak.ulsan.ac.kr/handle/2021.oak/7164
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_doaj_primary_oai_doaj_org_article_4f71769b43da4ae2a10dadce8fbefd82&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,Contribution%20of%20p53%20in%20sensitivity%20to%20EGFR%20tyrosine%20kinase%20inhibitors%20in%20non-small%20cell%20lung%20cancer&offset=0&pcAvailability=true
Publisher
SCIENTIFIC REPORTS
Location
영국
Language
영어
ISSN
2045-2322
Citation Volume
11
Citation Number
1
Citation Start Page
0
Citation End Page
0
Appears in Collections:
Medicine > Medicine
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