JNK pathway suppression mediates insensitivity to combination endocrine therapy and CDK4/6 inhibition in ER+ breast cancer
Abstract CDK4/6 inhibitors in combination with endocrine therapy are now used as front-line treatment for patients with estrogen-receptor positive (ER+) breast cancer. While this combination improves overall survival, the mechanisms of disease progression remain poorly understood. Here, we performed...
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BMC
2025-08-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-025-03466-9 |
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| author | Sarah Alexandrou Christine S. Lee Kristine J. Fernandez Celine E. Wiharja Leila Eshraghi John Reeves Daniel A. Reed Neil Portman Zoe Phan Heloisa H. Milioli Iva Nikolic Antonia L. Cadell David R. Croucher Kaylene J. Simpson Elgene Lim Theresa E. Hickey Ewan K. A. Millar Carla L. Alves Henrik J. Ditzel C. Elizabeth Caldon |
| author_facet | Sarah Alexandrou Christine S. Lee Kristine J. Fernandez Celine E. Wiharja Leila Eshraghi John Reeves Daniel A. Reed Neil Portman Zoe Phan Heloisa H. Milioli Iva Nikolic Antonia L. Cadell David R. Croucher Kaylene J. Simpson Elgene Lim Theresa E. Hickey Ewan K. A. Millar Carla L. Alves Henrik J. Ditzel C. Elizabeth Caldon |
| author_sort | Sarah Alexandrou |
| collection | DOAJ |
| description | Abstract CDK4/6 inhibitors in combination with endocrine therapy are now used as front-line treatment for patients with estrogen-receptor positive (ER+) breast cancer. While this combination improves overall survival, the mechanisms of disease progression remain poorly understood. Here, we performed unbiased genome-wide CRISPR/Cas9 knockout screens using endocrine sensitive ER+ breast cancer cells to identify novel drivers of resistance to combination endocrine therapy (tamoxifen) and CDK4/6 inhibitor (palbociclib) treatment. Our screens identified the inactivation of JNK signalling, including loss of the kinase MAP2K7, as a key driver of drug insensitivity. We developed multiple CRISPR/Cas9 knockout ER+ breast cancer cell lines (MCF-7 and T-47D) to investigate the effects of MAP2K7 and downstream MAPK8 and MAPK9 loss. MAP2K7 knockout increased metastatic burden in vivo and led to impaired JNK-mediated stress responses, as well as promoting cell survival and reducing senescence entry following endocrine therapy and CDK4/6 inhibitor treatment. Mechanistically, this occurred via loss of the AP-1 transcription factor c-JUN, leading to an attenuated response to combination endocrine therapy plus CDK4/6 inhibition. Furthermore, analysis of clinical datasets found that inactivation of the JNK pathway was associated with increased metastatic burden, and low pJNKT183/Y185 activity correlated with a poorer response to systemic endocrine and CDK4/6 inhibitor therapies in both early-stage and metastatic ER+ breast cancer cohorts. Overall, we demonstrate that suppression of JNK signalling enables persistent growth during combined endocrine therapy and CDK4/6 inhibition. Our data provides the pre-clinical rationale to stratify patients based on JNK pathway activity prior to receiving combination endocrine therapy and CDK4/6 inhibition. |
| format | Article |
| id | doaj-art-07f90e5a771e447aaf4d2fba54a38e7a |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-07f90e5a771e447aaf4d2fba54a38e7a2025-08-24T11:57:29ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-08-0144112410.1186/s13046-025-03466-9JNK pathway suppression mediates insensitivity to combination endocrine therapy and CDK4/6 inhibition in ER+ breast cancerSarah Alexandrou0Christine S. Lee1Kristine J. Fernandez2Celine E. Wiharja3Leila Eshraghi4John Reeves5Daniel A. Reed6Neil Portman7Zoe Phan8Heloisa H. Milioli9Iva Nikolic10Antonia L. Cadell11David R. Croucher12Kaylene J. Simpson13Elgene Lim14Theresa E. Hickey15Ewan K. A. Millar16Carla L. Alves17Henrik J. Ditzel18C. Elizabeth Caldon19Garvan Institute of Medical ResearchGarvan Institute of Medical ResearchGarvan Institute of Medical ResearchGarvan Institute of Medical ResearchGarvan Institute of Medical ResearchGarvan Institute of Medical ResearchGarvan Institute of Medical ResearchGarvan Institute of Medical ResearchGarvan Institute of Medical ResearchGarvan Institute of Medical ResearchVictorian Centre for Functional Genomics, Peter MacCallum Cancer CentreGarvan Institute of Medical ResearchGarvan Institute of Medical ResearchVictorian Centre for Functional Genomics, Peter MacCallum Cancer CentreGarvan Institute of Medical ResearchDame Roma Mitchell Cancer Research Adelaide Medical School Laboratories, University of AdelaideDepartment of Anatomical Pathology, NSW Health Pathology, St George HospitalDepartment of Molecular Medicine, Cancer Research Unit, University of Southern DenmarkDepartment of Molecular Medicine, Cancer Research Unit, University of Southern DenmarkGarvan Institute of Medical ResearchAbstract CDK4/6 inhibitors in combination with endocrine therapy are now used as front-line treatment for patients with estrogen-receptor positive (ER+) breast cancer. While this combination improves overall survival, the mechanisms of disease progression remain poorly understood. Here, we performed unbiased genome-wide CRISPR/Cas9 knockout screens using endocrine sensitive ER+ breast cancer cells to identify novel drivers of resistance to combination endocrine therapy (tamoxifen) and CDK4/6 inhibitor (palbociclib) treatment. Our screens identified the inactivation of JNK signalling, including loss of the kinase MAP2K7, as a key driver of drug insensitivity. We developed multiple CRISPR/Cas9 knockout ER+ breast cancer cell lines (MCF-7 and T-47D) to investigate the effects of MAP2K7 and downstream MAPK8 and MAPK9 loss. MAP2K7 knockout increased metastatic burden in vivo and led to impaired JNK-mediated stress responses, as well as promoting cell survival and reducing senescence entry following endocrine therapy and CDK4/6 inhibitor treatment. Mechanistically, this occurred via loss of the AP-1 transcription factor c-JUN, leading to an attenuated response to combination endocrine therapy plus CDK4/6 inhibition. Furthermore, analysis of clinical datasets found that inactivation of the JNK pathway was associated with increased metastatic burden, and low pJNKT183/Y185 activity correlated with a poorer response to systemic endocrine and CDK4/6 inhibitor therapies in both early-stage and metastatic ER+ breast cancer cohorts. Overall, we demonstrate that suppression of JNK signalling enables persistent growth during combined endocrine therapy and CDK4/6 inhibition. Our data provides the pre-clinical rationale to stratify patients based on JNK pathway activity prior to receiving combination endocrine therapy and CDK4/6 inhibition.https://doi.org/10.1186/s13046-025-03466-9CDK4/6 inhibitionPalbociclibER+ breast cancerJNK signallingEndocrine therapy |
| spellingShingle | Sarah Alexandrou Christine S. Lee Kristine J. Fernandez Celine E. Wiharja Leila Eshraghi John Reeves Daniel A. Reed Neil Portman Zoe Phan Heloisa H. Milioli Iva Nikolic Antonia L. Cadell David R. Croucher Kaylene J. Simpson Elgene Lim Theresa E. Hickey Ewan K. A. Millar Carla L. Alves Henrik J. Ditzel C. Elizabeth Caldon JNK pathway suppression mediates insensitivity to combination endocrine therapy and CDK4/6 inhibition in ER+ breast cancer Journal of Experimental & Clinical Cancer Research CDK4/6 inhibition Palbociclib ER+ breast cancer JNK signalling Endocrine therapy |
| title | JNK pathway suppression mediates insensitivity to combination endocrine therapy and CDK4/6 inhibition in ER+ breast cancer |
| title_full | JNK pathway suppression mediates insensitivity to combination endocrine therapy and CDK4/6 inhibition in ER+ breast cancer |
| title_fullStr | JNK pathway suppression mediates insensitivity to combination endocrine therapy and CDK4/6 inhibition in ER+ breast cancer |
| title_full_unstemmed | JNK pathway suppression mediates insensitivity to combination endocrine therapy and CDK4/6 inhibition in ER+ breast cancer |
| title_short | JNK pathway suppression mediates insensitivity to combination endocrine therapy and CDK4/6 inhibition in ER+ breast cancer |
| title_sort | jnk pathway suppression mediates insensitivity to combination endocrine therapy and cdk4 6 inhibition in er breast cancer |
| topic | CDK4/6 inhibition Palbociclib ER+ breast cancer JNK signalling Endocrine therapy |
| url | https://doi.org/10.1186/s13046-025-03466-9 |
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