Identification of the Notch ligand DLK1 as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma
Abstract While immunotherapeutic targeting of cell surface proteins is an increasingly effective cancer therapy, identification of new surface proteins, particularly those with biological importance, is critical. Here, we uncover delta-like non-canonical Notch ligand 1 (DLK1) as a cell surface prote...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60649-w |
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| author | Nai-Yun Sun Suresh Kumar Yoo Sun Kim Diana Varghese Arnulfo Mendoza Rosa Nguyen Reona Okada Karlyne Reilly Brigitte Widemann Yves Pommier Fathi Elloumi Anjali Dhall Daiki Taniyama Mayank Patel Etan Aber Cristina F. Contreras Rosandra N. Kaplan Katja Kiseljak-Vassiliades Margaret E. Wierman Dan Martinez Jennifer Pogoriler Amber K. Hamilton Sharon J. Diskin John M. Maris Robert W. Robey Michael M. Gottesman Jaydira Del Rivero Nitin Roper |
| author_facet | Nai-Yun Sun Suresh Kumar Yoo Sun Kim Diana Varghese Arnulfo Mendoza Rosa Nguyen Reona Okada Karlyne Reilly Brigitte Widemann Yves Pommier Fathi Elloumi Anjali Dhall Daiki Taniyama Mayank Patel Etan Aber Cristina F. Contreras Rosandra N. Kaplan Katja Kiseljak-Vassiliades Margaret E. Wierman Dan Martinez Jennifer Pogoriler Amber K. Hamilton Sharon J. Diskin John M. Maris Robert W. Robey Michael M. Gottesman Jaydira Del Rivero Nitin Roper |
| author_sort | Nai-Yun Sun |
| collection | DOAJ |
| description | Abstract While immunotherapeutic targeting of cell surface proteins is an increasingly effective cancer therapy, identification of new surface proteins, particularly those with biological importance, is critical. Here, we uncover delta-like non-canonical Notch ligand 1 (DLK1) as a cell surface protein with limited normal tissue expression and high expression in multiple refractory adult metastatic cancers including small cell lung cancer (SCLC) and adrenocortical carcinoma (ACC), a rare cancer with few effective therapies. In ACC, ADCT-701, a DLK1 targeting antibody-drug conjugate (ADC), shows in vitro and in vivo activity but is overall limited due to high expression and activity of the drug efflux protein ABCB1 (MDR1, P-glycoprotein). In contrast, ADCT-701 induces complete responses in DLK1+ ACC and SCLC in vivo models with low or no ABCB1 expression. Genetic deletion of DLK1 in ACC dramatically downregulates ABCB1 and increases ADC payload and chemotherapy sensitivity through NOTCH1-mediated transdifferentiation. This work identifies DLK1 as an immunotherapeutic target that regulates tumor cell plasticity and chemoresistance in ACC and supports an active phase I clinical trial targeting DLK1 with an ADC in ACC and neuroendocrine neoplasms (NCT06041516). |
| format | Article |
| id | doaj-art-c200c25bdb1d4bc69320d5bdbeaafba7 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c200c25bdb1d4bc69320d5bdbeaafba72025-08-20T03:45:35ZengNature PortfolioNature Communications2041-17232025-07-0116111510.1038/s41467-025-60649-wIdentification of the Notch ligand DLK1 as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinomaNai-Yun Sun0Suresh Kumar1Yoo Sun Kim2Diana Varghese3Arnulfo Mendoza4Rosa Nguyen5Reona Okada6Karlyne Reilly7Brigitte Widemann8Yves Pommier9Fathi Elloumi10Anjali Dhall11Daiki Taniyama12Mayank Patel13Etan Aber14Cristina F. Contreras15Rosandra N. Kaplan16Katja Kiseljak-Vassiliades17Margaret E. Wierman18Dan Martinez19Jennifer Pogoriler20Amber K. Hamilton21Sharon J. Diskin22John M. Maris23Robert W. Robey24Michael M. Gottesman25Jaydira Del Rivero26Nitin Roper27Developmental Therapeutics Branch, Center for Cancer Research, NCIDevelopmental Therapeutics Branch, Center for Cancer Research, NCIDevelopmental Therapeutics Branch, Center for Cancer Research, NCIDevelopmental Therapeutics Branch, Center for Cancer Research, NCIPediatric Oncology Branch, Center for Cancer Research, NCIPediatric Oncology Branch, Center for Cancer Research, NCIPediatric Oncology Branch, Center for Cancer Research, NCIPediatric Oncology Branch, Center for Cancer Research, NCIPediatric Oncology Branch, Center for Cancer Research, NCIDevelopmental Therapeutics Branch, Center for Cancer Research, NCIDevelopmental Therapeutics Branch, Center for Cancer Research, NCIDevelopmental Therapeutics Branch, Center for Cancer Research, NCIDevelopmental Therapeutics Branch, Center for Cancer Research, NCILaboratory of Pathology, Center for Cancer Research, NCIPediatric Oncology Branch, Center for Cancer Research, NCIPediatric Oncology Branch, Center for Cancer Research, NCIPediatric Oncology Branch, Center for Cancer Research, NCIDepartment of Medicine-Endocrinology/Metabolism/Diabetes, University of Colorado, Anschutz Medical CampusDepartment of Medicine-Endocrinology/Metabolism/Diabetes, University of Colorado, Anschutz Medical CampusDepartment of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia and Perelman School of Medicine, University of PennsylvaniaDepartment of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia and Perelman School of Medicine, University of PennsylvaniaDepartment of Pediatrics, Perelman School of Medicine, University of Pennsylvania, and Children’s Hospital of PhiladelphiaDepartment of Pediatrics, Perelman School of Medicine, University of Pennsylvania, and Children’s Hospital of PhiladelphiaDepartment of Pediatrics, Perelman School of Medicine, University of Pennsylvania, and Children’s Hospital of PhiladelphiaLaboratory of Cell Biology, Center for Cancer Research, NCILaboratory of Cell Biology, Center for Cancer Research, NCIDevelopmental Therapeutics Branch, Center for Cancer Research, NCIDevelopmental Therapeutics Branch, Center for Cancer Research, NCIAbstract While immunotherapeutic targeting of cell surface proteins is an increasingly effective cancer therapy, identification of new surface proteins, particularly those with biological importance, is critical. Here, we uncover delta-like non-canonical Notch ligand 1 (DLK1) as a cell surface protein with limited normal tissue expression and high expression in multiple refractory adult metastatic cancers including small cell lung cancer (SCLC) and adrenocortical carcinoma (ACC), a rare cancer with few effective therapies. In ACC, ADCT-701, a DLK1 targeting antibody-drug conjugate (ADC), shows in vitro and in vivo activity but is overall limited due to high expression and activity of the drug efflux protein ABCB1 (MDR1, P-glycoprotein). In contrast, ADCT-701 induces complete responses in DLK1+ ACC and SCLC in vivo models with low or no ABCB1 expression. Genetic deletion of DLK1 in ACC dramatically downregulates ABCB1 and increases ADC payload and chemotherapy sensitivity through NOTCH1-mediated transdifferentiation. This work identifies DLK1 as an immunotherapeutic target that regulates tumor cell plasticity and chemoresistance in ACC and supports an active phase I clinical trial targeting DLK1 with an ADC in ACC and neuroendocrine neoplasms (NCT06041516).https://doi.org/10.1038/s41467-025-60649-w |
| spellingShingle | Nai-Yun Sun Suresh Kumar Yoo Sun Kim Diana Varghese Arnulfo Mendoza Rosa Nguyen Reona Okada Karlyne Reilly Brigitte Widemann Yves Pommier Fathi Elloumi Anjali Dhall Daiki Taniyama Mayank Patel Etan Aber Cristina F. Contreras Rosandra N. Kaplan Katja Kiseljak-Vassiliades Margaret E. Wierman Dan Martinez Jennifer Pogoriler Amber K. Hamilton Sharon J. Diskin John M. Maris Robert W. Robey Michael M. Gottesman Jaydira Del Rivero Nitin Roper Identification of the Notch ligand DLK1 as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma Nature Communications |
| title | Identification of the Notch ligand DLK1 as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma |
| title_full | Identification of the Notch ligand DLK1 as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma |
| title_fullStr | Identification of the Notch ligand DLK1 as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma |
| title_full_unstemmed | Identification of the Notch ligand DLK1 as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma |
| title_short | Identification of the Notch ligand DLK1 as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma |
| title_sort | identification of the notch ligand dlk1 as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma |
| url | https://doi.org/10.1038/s41467-025-60649-w |
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