JNK pathway suppression mediates insensitivity to combination endocrine therapy and CDK4/6 inhibition in ER+ breast cancer
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...
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| Veröffentlicht in: | Journal of experimental & clinical cancer research Jg. 44; H. 1; S. 244 - 24 |
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| Format: | Journal Article |
| Sprache: | Englisch |
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BioMed Central
19.08.2025
BioMed Central Ltd Springer Nature B.V BMC |
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| ISSN: | 1756-9966, 0392-9078, 1756-9966 |
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| 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 pJNK
T183/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.
Statement of translational relevance
Combined use of endocrine therapy and CDK4/6 inhibition is now standard-of-care for patients with ER+ breast cancer, including those with high-risk early-stage and advanced disease. However, insensitivity or resistance to this therapeutic combination presents a growing clinical challenge as the mechanisms driving drug insensitivity remain poorly understood. Here, we have identified inactivation of JNK signalling, specifically loss of the JNK kinase
MAP2K7
, as a major determinant of insensitivity to combined endocrine therapy and CDK4/6 inhibition in ER+ breast cancer. We uncovered that
MAP2K7
loss augments tumour survival in vitro and in vivo. This occurs via disruption of activator protein-1 (AP-1) transcription factors, and thus prevents the induction of therapy-induced senescence and JNK-activated stress response. These findings reveal a critical tumour suppressor role for the JNK pathway in ER+ breast cancer and suggests that patients with deficient JNK signalling may derive limited benefit from combination endocrine therapy plus CDK4/6 inhibition. This supports the rationale for pre-treatment assessment of JNK pathway activity and cautions against the development of JNK inhibitors for this setting. |
|---|---|
| AbstractList | 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. 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 pJNK.sup.T183/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. 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 pJNK 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. 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. Combined use of endocrine therapy and CDK4/6 inhibition is now standard-of-care for patients with ER+ breast cancer, including those with high-risk early-stage and advanced disease. However, insensitivity or resistance to this therapeutic combination presents a growing clinical challenge as the mechanisms driving drug insensitivity remain poorly understood. Here, we have identified inactivation of JNK signalling, specifically loss of the JNK kinase MAP2K7, as a major determinant of insensitivity to combined endocrine therapy and CDK4/6 inhibition in ER+ breast cancer. We uncovered that MAP2K7 loss augments tumour survival in vitro and in vivo. This occurs via disruption of activator protein-1 (AP-1) transcription factors, and thus prevents the induction of therapy-induced senescence and JNK-activated stress response. These findings reveal a critical tumour suppressor role for the JNK pathway in ER+ breast cancer and suggests that patients with deficient JNK signalling may derive limited benefit from combination endocrine therapy plus CDK4/6 inhibition. This supports the rationale for pre-treatment assessment of JNK pathway activity and cautions against the development of JNK inhibitors for this setting. 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 pJNK T183/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. Statement of translational relevance Combined use of endocrine therapy and CDK4/6 inhibition is now standard-of-care for patients with ER+ breast cancer, including those with high-risk early-stage and advanced disease. However, insensitivity or resistance to this therapeutic combination presents a growing clinical challenge as the mechanisms driving drug insensitivity remain poorly understood. Here, we have identified inactivation of JNK signalling, specifically loss of the JNK kinase MAP2K7 , as a major determinant of insensitivity to combined endocrine therapy and CDK4/6 inhibition in ER+ breast cancer. We uncovered that MAP2K7 loss augments tumour survival in vitro and in vivo. This occurs via disruption of activator protein-1 (AP-1) transcription factors, and thus prevents the induction of therapy-induced senescence and JNK-activated stress response. These findings reveal a critical tumour suppressor role for the JNK pathway in ER+ breast cancer and suggests that patients with deficient JNK signalling may derive limited benefit from combination endocrine therapy plus CDK4/6 inhibition. This supports the rationale for pre-treatment assessment of JNK pathway activity and cautions against the development of JNK inhibitors for this setting. 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 pJNK.sup.T183/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. Keywords: CDK4/6 inhibition, Palbociclib, ER+ breast cancer, JNK signalling, Endocrine therapy 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.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. 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 pJNK T183/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. 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. |
| ArticleNumber | 244 |
| Audience | Academic |
| Author | Alexandrou, Sarah Wiharja, Celine E. Lee, Christine S. Lim, Elgene Simpson, Kaylene J. Ditzel, Henrik J. Portman, Neil Eshraghi, Leila Croucher, David R. Fernandez, Kristine J. Reeves, John Hickey, Theresa E. Cadell, Antonia L. Alves, Carla L. Caldon, C. Elizabeth Phan, Zoe Milioli, Heloisa H. Nikolic, Iva Reed, Daniel A. Millar, Ewan K. A. |
| Author_xml | – sequence: 1 givenname: Sarah surname: Alexandrou fullname: Alexandrou, Sarah organization: Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney – sequence: 2 givenname: Christine S. surname: Lee fullname: Lee, Christine S. organization: Garvan Institute of Medical Research – sequence: 3 givenname: Kristine J. surname: Fernandez fullname: Fernandez, Kristine J. organization: Garvan Institute of Medical Research – sequence: 4 givenname: Celine E. surname: Wiharja fullname: Wiharja, Celine E. organization: Garvan Institute of Medical Research – sequence: 5 givenname: Leila surname: Eshraghi fullname: Eshraghi, Leila organization: Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney – sequence: 6 givenname: John surname: Reeves fullname: Reeves, John organization: Garvan Institute of Medical Research – sequence: 7 givenname: Daniel A. surname: Reed fullname: Reed, Daniel A. organization: Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney – sequence: 8 givenname: Neil surname: Portman fullname: Portman, Neil organization: Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney – sequence: 9 givenname: Zoe surname: Phan fullname: Phan, Zoe organization: Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney – sequence: 10 givenname: Heloisa H. surname: Milioli fullname: Milioli, Heloisa H. organization: Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney – sequence: 11 givenname: Iva surname: Nikolic fullname: Nikolic, Iva organization: Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre – sequence: 12 givenname: Antonia L. surname: Cadell fullname: Cadell, Antonia L. organization: Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney – sequence: 13 givenname: David R. surname: Croucher fullname: Croucher, David R. organization: Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney – sequence: 14 givenname: Kaylene J. surname: Simpson fullname: Simpson, Kaylene J. organization: Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Sir Peter MacCallum Department of Oncology, Department of Biochemistry and Pharmacology, University of Melbourne – sequence: 15 givenname: Elgene surname: Lim fullname: Lim, Elgene organization: Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney – sequence: 16 givenname: Theresa E. surname: Hickey fullname: Hickey, Theresa E. organization: Dame Roma Mitchell Cancer Research Adelaide Medical School Laboratories, University of Adelaide – sequence: 17 givenname: Ewan K. A. surname: Millar fullname: Millar, Ewan K. A. organization: Department of Anatomical Pathology, NSW Health Pathology, St George Hospital, St George & Sutherland Campus, School of Clinical Medicine, UNSW Sydney – sequence: 18 givenname: Carla L. surname: Alves fullname: Alves, Carla L. organization: Department of Molecular Medicine, Cancer Research Unit, University of Southern Denmark – sequence: 19 givenname: Henrik J. surname: Ditzel fullname: Ditzel, Henrik J. organization: Department of Molecular Medicine, Cancer Research Unit, University of Southern Denmark, Department of Oncology, Odense University Hospital – sequence: 20 givenname: C. Elizabeth surname: Caldon fullname: Caldon, C. Elizabeth email: l.caldon@garvan.org.au organization: Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/40826108$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
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| DOI | 10.1186/s13046-025-03466-9 |
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| Keywords | Endocrine therapy ER+ breast cancer JNK signalling Palbociclib CDK4/6 inhibition |
| Language | English |
| License | 2025. The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
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| Snippet | CDK4/6 inhibitors in combination with endocrine therapy are now used as front-line treatment for patients with estrogen-receptor positive (ER+) breast cancer.... CDK4/6 inhibitors in combination with endocrine therapy are now used as front-line treatment for patients with estrogen-receptor positive (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... |
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| SubjectTerms | Animals Antimitotic agents Antineoplastic agents Apoptosis Biomedical and Life Sciences Biomedicine Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Cancer Research Cancer therapies CDK4/6 inhibition Cell growth Cell Line, Tumor CRISPR Cyclin-Dependent Kinase 4 - antagonists & inhibitors Cyclin-Dependent Kinase 6 - antagonists & inhibitors Cyclin-dependent kinases Cytokeratin Development and progression Drug Resistance, Neoplasm Endocrine therapy ER+ breast cancer Estrogen Female Genomes Genomics Humans Immunology JNK signalling Kinases MAP Kinase Signaling System - drug effects Medical research Metabolism Metastasis Mice Oncology Palbociclib Piperazines Plasmids Protein Kinase Inhibitors - pharmacology Pyridines - pharmacology Receptors, Estrogen - metabolism Tamoxifen - pharmacology Xenograft Model Antitumor Assays |
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| Title | JNK pathway suppression mediates insensitivity to combination endocrine therapy and CDK4/6 inhibition in ER+ breast cancer |
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