Systematic omics analysis identifies CCR6 as a therapeutic target to overcome cancer resistance to EGFR inhibitors
Summary: Epidermal growth factor receptor inhibitors (EGFRi) have exhibited promising clinical outcomes in the treatment of various cancers. However, their widespread application has been limited by low patient eligibility and the emergence of resistance. Leveraging a multi-omics approach (>1000...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-04-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224006692 |
| _version_ | 1827311799977902080 |
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| author | Eun-Ji Kwon Hyuk-Jin Cha Haeseung Lee |
| author_facet | Eun-Ji Kwon Hyuk-Jin Cha Haeseung Lee |
| author_sort | Eun-Ji Kwon |
| collection | DOAJ |
| description | Summary: Epidermal growth factor receptor inhibitors (EGFRi) have exhibited promising clinical outcomes in the treatment of various cancers. However, their widespread application has been limited by low patient eligibility and the emergence of resistance. Leveraging a multi-omics approach (>1000 cancer cell lines), we explored molecular signatures linked to EGFRi responsiveness and found that expression signatures involved in the estrogen response could recapitulate cancer cell dependency on EGFR, a phenomenon not solely attributable to EGFR-activating mutations. By correlating genome-wide function screening data with EGFRi responses, we identified chemokine receptor 6 (CCR6) as a potential druggable target to mitigate EGFRi resistance. In isogenic cell models, pharmacological inhibition of CCR6 effectively reversed acquired EGFRi resistance, disrupting mitochondrial oxidative phosphorylation, a cellular process commonly associated with therapy resistance. Our data-driven strategy unveils drug-response biomarkers and therapeutic targets for resistance, thus potentially expanding EGFRi applicability and efficacy. |
| first_indexed | 2024-04-24T20:24:46Z |
| format | Article |
| id | doaj.art-60e8dc7c49cd4053824e4b16613841e5 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-24T20:24:46Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-60e8dc7c49cd4053824e4b16613841e52024-03-22T05:40:25ZengElsevieriScience2589-00422024-04-01274109448Systematic omics analysis identifies CCR6 as a therapeutic target to overcome cancer resistance to EGFR inhibitorsEun-Ji Kwon0Hyuk-Jin Cha1Haeseung Lee2College of Pharmacy, Seoul National University, Seoul 08826, Republic of KoreaCollege of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Corresponding authorDepartment of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea; Corresponding authorSummary: Epidermal growth factor receptor inhibitors (EGFRi) have exhibited promising clinical outcomes in the treatment of various cancers. However, their widespread application has been limited by low patient eligibility and the emergence of resistance. Leveraging a multi-omics approach (>1000 cancer cell lines), we explored molecular signatures linked to EGFRi responsiveness and found that expression signatures involved in the estrogen response could recapitulate cancer cell dependency on EGFR, a phenomenon not solely attributable to EGFR-activating mutations. By correlating genome-wide function screening data with EGFRi responses, we identified chemokine receptor 6 (CCR6) as a potential druggable target to mitigate EGFRi resistance. In isogenic cell models, pharmacological inhibition of CCR6 effectively reversed acquired EGFRi resistance, disrupting mitochondrial oxidative phosphorylation, a cellular process commonly associated with therapy resistance. Our data-driven strategy unveils drug-response biomarkers and therapeutic targets for resistance, thus potentially expanding EGFRi applicability and efficacy.http://www.sciencedirect.com/science/article/pii/S2589004224006692Integrative aspects of cell biologyCancer systems biologyCancerOmics |
| spellingShingle | Eun-Ji Kwon Hyuk-Jin Cha Haeseung Lee Systematic omics analysis identifies CCR6 as a therapeutic target to overcome cancer resistance to EGFR inhibitors iScience Integrative aspects of cell biology Cancer systems biology Cancer Omics |
| title | Systematic omics analysis identifies CCR6 as a therapeutic target to overcome cancer resistance to EGFR inhibitors |
| title_full | Systematic omics analysis identifies CCR6 as a therapeutic target to overcome cancer resistance to EGFR inhibitors |
| title_fullStr | Systematic omics analysis identifies CCR6 as a therapeutic target to overcome cancer resistance to EGFR inhibitors |
| title_full_unstemmed | Systematic omics analysis identifies CCR6 as a therapeutic target to overcome cancer resistance to EGFR inhibitors |
| title_short | Systematic omics analysis identifies CCR6 as a therapeutic target to overcome cancer resistance to EGFR inhibitors |
| title_sort | systematic omics analysis identifies ccr6 as a therapeutic target to overcome cancer resistance to egfr inhibitors |
| topic | Integrative aspects of cell biology Cancer systems biology Cancer Omics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224006692 |
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