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Elevated expression of miR-494-3p is associated with resistance to osimertinib in EGFR T790M-positive non-small cell lung cancer.
Kazmierczak, Dominika; Eide, Inger Johanne Zwicky; Gencheva, Radosveta; Lai, Yi; Lewensohn, Rolf; Tsakonas, Georgios; Grundberg, Oscar; de Petris, Luigi; McGowan, Marc; Brustugun, Odd Terje; Ekman, Simon; Hydbring, Per.
Afiliación
  • Kazmierczak D; Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
  • Eide IJZ; Section of Oncology, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway.
  • Gencheva R; Faculty of Medicine, University of Oslo, Oslo, Norway.
  • Lai Y; Section of Cancer Genetics, Inst of Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
  • Lewensohn R; Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
  • Tsakonas G; Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
  • Grundberg O; Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
  • de Petris L; Thoracic Oncology Center, Karolinska University Hospital, Stockholm, Sweden.
  • McGowan M; Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
  • Brustugun OT; Thoracic Oncology Center, Karolinska University Hospital, Stockholm, Sweden.
  • Ekman S; Thoracic Oncology Center, Karolinska University Hospital, Stockholm, Sweden.
  • Hydbring P; Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
Transl Lung Cancer Res ; 11(5): 722-734, 2022 May.
Article en En | MEDLINE | ID: mdl-35693293
Background: Non-small cell lung cancer (NSCLC) harboring activating mutations in the gene encoding epidermal growth factor receptor (EGFR) is amenable for targeted therapy with tyrosine kinase inhibitors (TKIs). Eventually, resistance to TKI-therapy occurs resulting in disease progression. A substantial fraction of resistance mechanisms is unknown and may involve alterations in the RNA or protein landscape. MicroRNAs (miRNAs) have been frequently suggested to play roles in various forms of cancer including NSCLC. However, a role of miRNAs in acquired resistance to EGFR TKIs remains elusive. In this work, we aimed to investigate the potential involvement of miRNAs in acquired resistance to the third-generation EGFR TKI osimertinib in NSCLC. Methods: We combined miRNA expression profiling with miRNA-inhibitory screening to identify miRNAs involved in conferring resistance to osimertinib. Finally, we validated our top miRNA candidate by profiling longitudinal plasma exosomal RNA from patients receiving osimertinib as second-line therapy in a clinical trial. Results: Various miRNAs displayed differential expression in parental versus osimertinib-refractory NSCLC cells. miRNA-inhibitory screening revealed miR-494-3p to partially confer resistance to osimertinib in vitro. Expression of miR-494-3p was significantly elevated in plasma sampled at disease progression compared to plasma sampled at treatment baseline in a cohort of 21 EGFR T790M-mutation positive NSCLC patients receiving osimertinib. Conclusions: Our results highlight the need for further therapeutic exploration of miR-494-3p in in vivo models of EGFR-mutant NSCLC.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies / Risk_factors_studies Idioma: En Revista: Transl Lung Cancer Res Año: 2022 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: China
Texto completo
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PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies / Risk_factors_studies Idioma: En Revista: Transl Lung Cancer Res Año: 2022 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: China