Plasma RNA profiling unveils transcriptional signatures associated with resistance to osimertinib in EGFR T790M positive non-small cell lung cancer patients
2022 Translational Lung Cancer Research. All rights reserved..
Background: Targeted therapy with tyrosine kinases inhibitors (TKIs) against epidermal growth factor receptor (EGFR) is part of routine clinical practice for EGFR mutant advanced non-small cell lung cancer (NSCLC) patients. These patients eventually develop resistance, frequently accompanied by a gatekeeper mutation, T790M. Osimertinib is a third-generation EGFR TKI displaying potency to the T790M resistance mutation. Here we aimed to analyze if exosomal RNAs, isolated from longitudinally sampled plasma of osimertinib-treated EGFR T790M NSCLC patients, could provide biomarkers of acquired resistance to osimertinib.
Methods: Plasma was collected at baseline and progression of disease from 20 patients treated with osimertinib in the multicenter phase II study TKI in Relapsed EGFR-mutated non-small cell lung cancer patients (TREM). Plasma was centrifuged at 16,000 g followed by exosomal RNA extraction using Qiagen exoRNeasy kit. RNA was subjected to transcriptomics analysis with Clariom D.
Results: Transcriptome profiling revealed differential expression [log2(fold-change) >0.25, false discovery rate (FDR) P<0.15, and P(interaction) >0.05] of 128 transcripts. We applied network enrichment analysis (NEA) at the pathway level in a large collection of functional gene sets. This overall enrichment analysis revealed alterations in pathways related to EGFR and PI3K as well as to syndecan and glypican pathways (NEA FDR <3×10-10). When applied to the 40 individual, sample-specific gene sets, the NEA detected 16 immune-related gene sets (FDR <0.25, P(interaction) >0.05 and NEA z-score exceeding 3 in at least one sample).
Conclusions: Our study demonstrates a potential usability of plasma-derived exosomal RNAs to characterize molecular phenotypes of emerging osimertinib resistance. Furthermore, it highlights the involvement of multiple RNA species in shaping the transcriptome landscape of osimertinib-refractory NSCLC patients.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
Translational lung cancer research - 11(2022), 10 vom: 12. Okt., Seite 2064-2078 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Alexeyenko, Andrey [VerfasserIn] |
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| Links: |
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| Themen: |
Epidermal growth factor receptor (EGFR) |
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| Anmerkungen: |
Date Revised 18.11.2022 published: Print Citation Status PubMed-not-MEDLINE |
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| doi: |
10.21037/tlcr-22-236 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM348998090 |
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| 100 | 1 | |a Alexeyenko, Andrey |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Plasma RNA profiling unveils transcriptional signatures associated with resistance to osimertinib in EGFR T790M positive non-small cell lung cancer patients |
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| 500 | |a published: Print | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a 2022 Translational Lung Cancer Research. All rights reserved. | ||
| 520 | |a Background: Targeted therapy with tyrosine kinases inhibitors (TKIs) against epidermal growth factor receptor (EGFR) is part of routine clinical practice for EGFR mutant advanced non-small cell lung cancer (NSCLC) patients. These patients eventually develop resistance, frequently accompanied by a gatekeeper mutation, T790M. Osimertinib is a third-generation EGFR TKI displaying potency to the T790M resistance mutation. Here we aimed to analyze if exosomal RNAs, isolated from longitudinally sampled plasma of osimertinib-treated EGFR T790M NSCLC patients, could provide biomarkers of acquired resistance to osimertinib | ||
| 520 | |a Methods: Plasma was collected at baseline and progression of disease from 20 patients treated with osimertinib in the multicenter phase II study TKI in Relapsed EGFR-mutated non-small cell lung cancer patients (TREM). Plasma was centrifuged at 16,000 g followed by exosomal RNA extraction using Qiagen exoRNeasy kit. RNA was subjected to transcriptomics analysis with Clariom D | ||
| 520 | |a Results: Transcriptome profiling revealed differential expression [log2(fold-change) >0.25, false discovery rate (FDR) P<0.15, and P(interaction) >0.05] of 128 transcripts. We applied network enrichment analysis (NEA) at the pathway level in a large collection of functional gene sets. This overall enrichment analysis revealed alterations in pathways related to EGFR and PI3K as well as to syndecan and glypican pathways (NEA FDR <3×10-10). When applied to the 40 individual, sample-specific gene sets, the NEA detected 16 immune-related gene sets (FDR <0.25, P(interaction) >0.05 and NEA z-score exceeding 3 in at least one sample) | ||
| 520 | |a Conclusions: Our study demonstrates a potential usability of plasma-derived exosomal RNAs to characterize molecular phenotypes of emerging osimertinib resistance. Furthermore, it highlights the involvement of multiple RNA species in shaping the transcriptome landscape of osimertinib-refractory NSCLC patients | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Non-small cell lung cancer (NSCLC) | |
| 650 | 4 | |a epidermal growth factor receptor (EGFR) | |
| 650 | 4 | |a exosomal RNA | |
| 650 | 4 | |a osimertinib | |
| 650 | 4 | |a transcriptome | |
| 700 | 1 | |a Brustugun, Odd Terje |e verfasserin |4 aut | |
| 700 | 1 | |a Eide, Inger Johanne Zwicky |e verfasserin |4 aut | |
| 700 | 1 | |a Gencheva, Radosveta |e verfasserin |4 aut | |
| 700 | 1 | |a Kosibaty, Zeinab |e verfasserin |4 aut | |
| 700 | 1 | |a Lai, Yi |e verfasserin |4 aut | |
| 700 | 1 | |a de Petris, Luigi |e verfasserin |4 aut | |
| 700 | 1 | |a Tsakonas, Georgios |e verfasserin |4 aut | |
| 700 | 1 | |a Grundberg, Oscar |e verfasserin |4 aut | |
| 700 | 1 | |a Franzen, Bo |e verfasserin |4 aut | |
| 700 | 1 | |a Viktorsson, Kristina |e verfasserin |4 aut | |
| 700 | 1 | |a Lewensohn, Rolf |e verfasserin |4 aut | |
| 700 | 1 | |a Hydbring, Per |e verfasserin |4 aut | |
| 700 | 1 | |a Ekman, Simon |e verfasserin |4 aut | |
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