This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research
Exosomes miR-184 and miR-3913-5p are involved in Osimertinib resistance in non-small cell lung cancer patients with exon 21 L858R mutation
Tangfeng Lv
Nanjing Jinling Hospital: East Region Military Command General Hospital
Corresponding Author
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
The third-generation of EGFR-TKI Osimertinib has become an important treatment option for patients with EGFR-mutant advanced NSCLC. In recent years, more and more studies have begun to pay attention to the ability of miRNAs in exosomes secreted by tumor cells to transmit resistance information. The mechanisms of exosomal miRNAs involved in Osimertinib resistance need to be studied.
Methods
We constructed an Osimertinib-resistant cell line H1975-OR, and collected the exosomes from the cells of the drug-resistant strain and the sensitive strain, and extracted respective RNA for sequencing. We also compared miRNAs in serum exosomes of three patients before and after resistance to Osimertinib. Enlarged samples were then validated in 64 NSCLC patients.
Results
Cluster analysis of target genes revealed that miRNAs in exosomes participate in Osimertinib resistance mechanisms through the activation of bypass pathways (RAS-MAPK pathway abnormality, PI3K pathway activation). MiR-184 and miR-3913-5p increased significantly in serum exosomes of patients with later Osimertinib resistance. These two miRNAs mainly cause EGFR resistance in two types of NSCLC patients, EGFR exon 21 L858R mutation and T790M positive.
Conclusions
Exosomes miR-184 and miR-3913-5p mainly cause Osimertinib resistance in lung cancer patients containing EGFR exon 21 L858R+ and T790M+. They are regarded as important biomarkers of third-generation EGFR-TKI resistance. This not only enriches the application of liquid biopsy in lung cancer drug resistance, but also provides a direction for future targeted drug research.
Keywords
Osimertinib (AZD9291), Exosome, miRNAs, Bypass pathway, NSCLC
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
This is a list of supplementary files associated with this preprint. Click to download.
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 08 Sep, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Learn more about our company.
This is a preprint. It has not completed peer review.
Research
Exosomes miR-184 and miR-3913-5p are involved in Osimertinib resistance in non-small cell lung cancer patients with exon 21 L858R mutation
Tangfeng Lv
Nanjing Jinling Hospital: East Region Military Command General Hospital
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 08 Sep, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
The third-generation of EGFR-TKI Osimertinib has become an important treatment option for patients with EGFR-mutant advanced NSCLC. In recent years, more and more studies have begun to pay attention to the ability of miRNAs in exosomes secreted by tumor cells to transmit resistance information. The mechanisms of exosomal miRNAs involved in Osimertinib resistance need to be studied.
Methods
We constructed an Osimertinib-resistant cell line H1975-OR, and collected the exosomes from the cells of the drug-resistant strain and the sensitive strain, and extracted respective RNA for sequencing. We also compared miRNAs in serum exosomes of three patients before and after resistance to Osimertinib. Enlarged samples were then validated in 64 NSCLC patients.
Results
Cluster analysis of target genes revealed that miRNAs in exosomes participate in Osimertinib resistance mechanisms through the activation of bypass pathways (RAS-MAPK pathway abnormality, PI3K pathway activation). MiR-184 and miR-3913-5p increased significantly in serum exosomes of patients with later Osimertinib resistance. These two miRNAs mainly cause EGFR resistance in two types of NSCLC patients, EGFR exon 21 L858R mutation and T790M positive.
Conclusions
Exosomes miR-184 and miR-3913-5p mainly cause Osimertinib resistance in lung cancer patients containing EGFR exon 21 L858R+ and T790M+. They are regarded as important biomarkers of third-generation EGFR-TKI resistance. This not only enriches the application of liquid biopsy in lung cancer drug resistance, but also provides a direction for future targeted drug research.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6