Ras-Related Protein Rab-32 and Thrombospondin 1 Confer Resistance to the EGFR Tyrosine Kinase Inhibitor Osimertinib by Activating Focal Adhesion Kinase in Non-Small Cell Lung Cancer
Treatment with the tyrosine kinase inhibitor (TKI) osimertinib is the standard of care for non-small cell lung cancer (NSCLC) patients with activating mutations in the epidermal growth factor receptor (EGFR). Osimertinib is also used in T790M-positive NSCLC that may occur de novo or be acquired foll...
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MDPI AG
2022-07-01
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| author | Zeinab Kosibaty Odd Terje Brustugun Inger Johanne Zwicky Eide Georgios Tsakonas Oscar Grundberg Luigi De Petris Marc McGowan Per Hydbring Simon Ekman |
| author_facet | Zeinab Kosibaty Odd Terje Brustugun Inger Johanne Zwicky Eide Georgios Tsakonas Oscar Grundberg Luigi De Petris Marc McGowan Per Hydbring Simon Ekman |
| author_sort | Zeinab Kosibaty |
| collection | DOAJ |
| description | Treatment with the tyrosine kinase inhibitor (TKI) osimertinib is the standard of care for non-small cell lung cancer (NSCLC) patients with activating mutations in the epidermal growth factor receptor (EGFR). Osimertinib is also used in T790M-positive NSCLC that may occur de novo or be acquired following first-line treatment with other EGFR TKIs (i.e., gefitinib, erlotinib, afatinib, or dacomitinib). However, patients treated with osimertinib have a high risk of developing resistance to the treatment. A substantial fraction of the mechanisms for resistance is unknown and may involve RNA and/or protein alterations. In this study, we investigated the full transcriptome of parental and osimertinib-resistant cell lines, revealing 131 differentially expressed genes. Knockdown screening of the genes upregulated in resistant cell lines uncovered eight genes to partly confer resistance to osimertinib. Among them, we detected the expression of Ras-related protein Rab-32 (RAB32) and thrombospondin 1 (THBS1) in plasmas sampled at baseline and at disease progression from EGFR-positive NSCLC patients treated with osimertinib. Both genes were upregulated in progression samples. Moreover, we found that knockdown of RAB32 and THBS1 reduced the expression of phosphorylated focal adhesion kinase (FAK). Combination of osimertinib with a FAK inhibitor resulted in synergistic toxicity in osimertinib-resistant cells, suggesting a potential therapeutic drug combination for overcoming resistance to osimertinib in NSCLC patients. |
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| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T10:21:41Z |
| publishDate | 2022-07-01 |
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| record_format | Article |
| series | Cancers |
| spelling | doaj.art-db834694be7d4b759fbd94adb1f203112023-12-01T21:59:24ZengMDPI AGCancers2072-66942022-07-011414343010.3390/cancers14143430Ras-Related Protein Rab-32 and Thrombospondin 1 Confer Resistance to the EGFR Tyrosine Kinase Inhibitor Osimertinib by Activating Focal Adhesion Kinase in Non-Small Cell Lung CancerZeinab Kosibaty0Odd Terje Brustugun1Inger Johanne Zwicky Eide2Georgios Tsakonas3Oscar Grundberg4Luigi De Petris5Marc McGowan6Per Hydbring7Simon Ekman8Department of Oncology and Pathology, Karolinska Institutet, 17164 Stockholm, SwedenSection of Oncology, Drammen Hospital, Vestre Viken Hospital Trust, 3004 Drammen, NorwaySection of Oncology, Drammen Hospital, Vestre Viken Hospital Trust, 3004 Drammen, NorwayDepartment of Oncology and Pathology, Karolinska Institutet, 17164 Stockholm, SwedenThoracic Oncology Center, Karolinska University Hospital, 17164 Stockholm, SwedenDepartment of Oncology and Pathology, Karolinska Institutet, 17164 Stockholm, SwedenDepartment of Cancer Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, 0424 Oslo, NorwayDepartment of Oncology and Pathology, Karolinska Institutet, 17164 Stockholm, SwedenDepartment of Oncology and Pathology, Karolinska Institutet, 17164 Stockholm, SwedenTreatment with the tyrosine kinase inhibitor (TKI) osimertinib is the standard of care for non-small cell lung cancer (NSCLC) patients with activating mutations in the epidermal growth factor receptor (EGFR). Osimertinib is also used in T790M-positive NSCLC that may occur de novo or be acquired following first-line treatment with other EGFR TKIs (i.e., gefitinib, erlotinib, afatinib, or dacomitinib). However, patients treated with osimertinib have a high risk of developing resistance to the treatment. A substantial fraction of the mechanisms for resistance is unknown and may involve RNA and/or protein alterations. In this study, we investigated the full transcriptome of parental and osimertinib-resistant cell lines, revealing 131 differentially expressed genes. Knockdown screening of the genes upregulated in resistant cell lines uncovered eight genes to partly confer resistance to osimertinib. Among them, we detected the expression of Ras-related protein Rab-32 (RAB32) and thrombospondin 1 (THBS1) in plasmas sampled at baseline and at disease progression from EGFR-positive NSCLC patients treated with osimertinib. Both genes were upregulated in progression samples. Moreover, we found that knockdown of RAB32 and THBS1 reduced the expression of phosphorylated focal adhesion kinase (FAK). Combination of osimertinib with a FAK inhibitor resulted in synergistic toxicity in osimertinib-resistant cells, suggesting a potential therapeutic drug combination for overcoming resistance to osimertinib in NSCLC patients.https://www.mdpi.com/2072-6694/14/14/3430non-small cell lung cancerexosomal RNAosimertinibtranscriptomeepidermal growth factor receptorRas-related protein Rab-32 |
| spellingShingle | Zeinab Kosibaty Odd Terje Brustugun Inger Johanne Zwicky Eide Georgios Tsakonas Oscar Grundberg Luigi De Petris Marc McGowan Per Hydbring Simon Ekman Ras-Related Protein Rab-32 and Thrombospondin 1 Confer Resistance to the EGFR Tyrosine Kinase Inhibitor Osimertinib by Activating Focal Adhesion Kinase in Non-Small Cell Lung Cancer Cancers non-small cell lung cancer exosomal RNA osimertinib transcriptome epidermal growth factor receptor Ras-related protein Rab-32 |
| title | Ras-Related Protein Rab-32 and Thrombospondin 1 Confer Resistance to the EGFR Tyrosine Kinase Inhibitor Osimertinib by Activating Focal Adhesion Kinase in Non-Small Cell Lung Cancer |
| title_full | Ras-Related Protein Rab-32 and Thrombospondin 1 Confer Resistance to the EGFR Tyrosine Kinase Inhibitor Osimertinib by Activating Focal Adhesion Kinase in Non-Small Cell Lung Cancer |
| title_fullStr | Ras-Related Protein Rab-32 and Thrombospondin 1 Confer Resistance to the EGFR Tyrosine Kinase Inhibitor Osimertinib by Activating Focal Adhesion Kinase in Non-Small Cell Lung Cancer |
| title_full_unstemmed | Ras-Related Protein Rab-32 and Thrombospondin 1 Confer Resistance to the EGFR Tyrosine Kinase Inhibitor Osimertinib by Activating Focal Adhesion Kinase in Non-Small Cell Lung Cancer |
| title_short | Ras-Related Protein Rab-32 and Thrombospondin 1 Confer Resistance to the EGFR Tyrosine Kinase Inhibitor Osimertinib by Activating Focal Adhesion Kinase in Non-Small Cell Lung Cancer |
| title_sort | ras related protein rab 32 and thrombospondin 1 confer resistance to the egfr tyrosine kinase inhibitor osimertinib by activating focal adhesion kinase in non small cell lung cancer |
| topic | non-small cell lung cancer exosomal RNA osimertinib transcriptome epidermal growth factor receptor Ras-related protein Rab-32 |
| url | https://www.mdpi.com/2072-6694/14/14/3430 |
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