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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| 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. |
| doi_str_mv | 10.3390/cancers14143430 |
| format | Article |
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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.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers14143430</identifier><identifier>PMID: 35884490</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Biopsy ; Cancer therapies ; Chemotherapy ; Drug resistance ; Drug therapy ; Enzyme inhibitors ; Epidermal growth factor ; Epidermal growth factor receptors ; Focal adhesion kinase ; Gefitinib ; Gene expression ; Genetic aspects ; Health aspects ; Kinases ; Lung cancer ; Lung cancer, Non-small cell ; Mutation ; Non-small cell lung carcinoma ; Patients ; Protein kinases ; Proteins ; Ras protein ; Small cell lung carcinoma ; Thrombospondin ; Toxicity ; Transcriptomes ; Tyrosine kinase inhibitors ; Wound healing</subject><ispartof>CANCERS, 2022-07, Vol.14 (14), p.3430</ispartof><rights>COPYRIGHT 2022 MDPI AG</rights><rights>2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). 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Moreover, we found that knockdown of RAB32 and THBS1 reduced the expression of phosphorylated focal adhesion kinase (FAK). 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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.</abstract><cop>Basel</cop><pub>MDPI AG</pub><pmid>35884490</pmid><doi>10.3390/cancers14143430</doi><orcidid>https://orcid.org/0000-0002-5153-8391</orcidid><orcidid>https://orcid.org/0000-0002-3527-762X</orcidid><orcidid>https://orcid.org/0000-0002-8343-6226</orcidid><orcidid>https://orcid.org/0000-0003-4397-7391</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MDPI - Multidisciplinary Digital Publishing Institute; NORA - Norwegian Open Research Archives; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; SWEPUB Freely available online; PubMed Central Open Access |
| subjects | Biopsy Cancer therapies Chemotherapy Drug resistance Drug therapy Enzyme inhibitors Epidermal growth factor Epidermal growth factor receptors Focal adhesion kinase Gefitinib Gene expression Genetic aspects Health aspects Kinases Lung cancer Lung cancer, Non-small cell Mutation Non-small cell lung carcinoma Patients Protein kinases Proteins Ras protein Small cell lung carcinoma Thrombospondin Toxicity Transcriptomes Tyrosine kinase inhibitors Wound healing |
| 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 |
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