Intratumor heterogeneity of EGFR expression mediates targeted therapy resistance and formation of drug tolerant microenvironment
Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are commonly used to treat non-small cell lung cancers with EGFR mutations, but drug resistance often emerges. Intratumor heterogeneity is a known cause of targeted therapy resistance and is considered a major factor in trea...
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| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55378-5 |
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| author | Bassel Alsaed Linh Lin Jieun Son Jiaqi Li Johannes Smolander Timothy Lopez Pinar Ö. Eser Atsuko Ogino Chiara Ambrogio Yoonji Eum Tran Thai Haiyun Wang Eva Sutinen Hilma Mutanen Hanna Duàn Nina Bobik Kristian Borenius William W. Feng Behnam Nabet Satu Mustjoki Sanna Laaksonen Benjamin K. Eschle Michael J. Poitras David Barbie Ilkka Ilonen Prafulla Gokhale Pasi A. Jänne Heidi M. Haikala |
| author_facet | Bassel Alsaed Linh Lin Jieun Son Jiaqi Li Johannes Smolander Timothy Lopez Pinar Ö. Eser Atsuko Ogino Chiara Ambrogio Yoonji Eum Tran Thai Haiyun Wang Eva Sutinen Hilma Mutanen Hanna Duàn Nina Bobik Kristian Borenius William W. Feng Behnam Nabet Satu Mustjoki Sanna Laaksonen Benjamin K. Eschle Michael J. Poitras David Barbie Ilkka Ilonen Prafulla Gokhale Pasi A. Jänne Heidi M. Haikala |
| author_sort | Bassel Alsaed |
| collection | DOAJ |
| description | Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are commonly used to treat non-small cell lung cancers with EGFR mutations, but drug resistance often emerges. Intratumor heterogeneity is a known cause of targeted therapy resistance and is considered a major factor in treatment failure. This study identifies clones of EGFR-mutant non-small cell lung tumors expressing low levels of both wild-type and mutant EGFR protein. These EGFR-low cells are intrinsically more tolerant to EGFR inhibitors, more invasive, and exhibit an epithelial-to-mesenchymal-like phenotype compared to their EGFR-high counterparts. The EGFR-low cells secrete Transforming growth factor beta (TGFβ) family cytokines, leading to increased recruitment of cancer-associated fibroblasts and immune suppression, thus contributing to the drug-tolerant tumor microenvironment. Notably, pharmacological induction of EGFR using epigenetic inhibitors sensitizes the resistant cells to EGFR inhibition. These findings suggest that intrinsic drug resistance can be prevented or reversed using combination therapies. |
| format | Article |
| id | doaj-art-c8a6f8fe8f964bb5979968858901dd63 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c8a6f8fe8f964bb5979968858901dd632025-08-20T02:53:53ZengNature PortfolioNature Communications2041-17232025-01-0116111710.1038/s41467-024-55378-5Intratumor heterogeneity of EGFR expression mediates targeted therapy resistance and formation of drug tolerant microenvironmentBassel Alsaed0Linh Lin1Jieun Son2Jiaqi Li3Johannes Smolander4Timothy Lopez5Pinar Ö. Eser6Atsuko Ogino7Chiara Ambrogio8Yoonji Eum9Tran Thai10Haiyun Wang11Eva Sutinen12Hilma Mutanen13Hanna Duàn14Nina Bobik15Kristian Borenius16William W. Feng17Behnam Nabet18Satu Mustjoki19Sanna Laaksonen20Benjamin K. Eschle21Michael J. Poitras22David Barbie23Ilkka Ilonen24Prafulla Gokhale25Pasi A. Jänne26Heidi M. Haikala27Translational Immunology Research Program (TRIMM), Research Programs Unit, Faculty of Medicine, University of HelsinkiTranslational Immunology Research Program (TRIMM), Research Programs Unit, Faculty of Medicine, University of HelsinkiDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteTranslational Immunology Research Program (TRIMM), Research Programs Unit, Faculty of Medicine, University of HelsinkiDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of TorinoDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteSchool of Life Sciences and Technology, Tongji UniversityIndividualized Drug Therapy Research Program, Faculty of Medicine, University of HelsinkiTranslational Immunology Research Program (TRIMM), Research Programs Unit, Faculty of Medicine, University of HelsinkiTranslational Immunology Research Program (TRIMM), Research Programs Unit, Faculty of Medicine, University of HelsinkiTranslational Immunology Research Program (TRIMM), Research Programs Unit, Faculty of Medicine, University of HelsinkiDepartment of General Thoracic and Esophageal Surgery, Heart and Lung Center, Helsinki University Hospital & University of HelsinkiDepartment of Medical Oncology, Dana-Farber Cancer InstituteHuman Biology Division, Fred Hutchinson Cancer CenterTranslational Immunology Research Program (TRIMM), Research Programs Unit, Faculty of Medicine, University of HelsinkiDepartment of Pathology, Helsinki University Hospital & University of HelsinkiDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteiCAN Digital Precision Cancer Medicine FlagshipDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteTranslational Immunology Research Program (TRIMM), Research Programs Unit, Faculty of Medicine, University of HelsinkiAbstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are commonly used to treat non-small cell lung cancers with EGFR mutations, but drug resistance often emerges. Intratumor heterogeneity is a known cause of targeted therapy resistance and is considered a major factor in treatment failure. This study identifies clones of EGFR-mutant non-small cell lung tumors expressing low levels of both wild-type and mutant EGFR protein. These EGFR-low cells are intrinsically more tolerant to EGFR inhibitors, more invasive, and exhibit an epithelial-to-mesenchymal-like phenotype compared to their EGFR-high counterparts. The EGFR-low cells secrete Transforming growth factor beta (TGFβ) family cytokines, leading to increased recruitment of cancer-associated fibroblasts and immune suppression, thus contributing to the drug-tolerant tumor microenvironment. Notably, pharmacological induction of EGFR using epigenetic inhibitors sensitizes the resistant cells to EGFR inhibition. These findings suggest that intrinsic drug resistance can be prevented or reversed using combination therapies.https://doi.org/10.1038/s41467-024-55378-5 |
| spellingShingle | Bassel Alsaed Linh Lin Jieun Son Jiaqi Li Johannes Smolander Timothy Lopez Pinar Ö. Eser Atsuko Ogino Chiara Ambrogio Yoonji Eum Tran Thai Haiyun Wang Eva Sutinen Hilma Mutanen Hanna Duàn Nina Bobik Kristian Borenius William W. Feng Behnam Nabet Satu Mustjoki Sanna Laaksonen Benjamin K. Eschle Michael J. Poitras David Barbie Ilkka Ilonen Prafulla Gokhale Pasi A. Jänne Heidi M. Haikala Intratumor heterogeneity of EGFR expression mediates targeted therapy resistance and formation of drug tolerant microenvironment Nature Communications |
| title | Intratumor heterogeneity of EGFR expression mediates targeted therapy resistance and formation of drug tolerant microenvironment |
| title_full | Intratumor heterogeneity of EGFR expression mediates targeted therapy resistance and formation of drug tolerant microenvironment |
| title_fullStr | Intratumor heterogeneity of EGFR expression mediates targeted therapy resistance and formation of drug tolerant microenvironment |
| title_full_unstemmed | Intratumor heterogeneity of EGFR expression mediates targeted therapy resistance and formation of drug tolerant microenvironment |
| title_short | Intratumor heterogeneity of EGFR expression mediates targeted therapy resistance and formation of drug tolerant microenvironment |
| title_sort | intratumor heterogeneity of egfr expression mediates targeted therapy resistance and formation of drug tolerant microenvironment |
| url | https://doi.org/10.1038/s41467-024-55378-5 |
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