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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Published in:	Journal of experimental & clinical cancer research Vol. 44; no. 1; pp. 244 - 24
Main Authors:	Alexandrou, Sarah, Lee, Christine S., Fernandez, Kristine J., Wiharja, Celine E., Eshraghi, Leila, Reeves, John, Reed, Daniel A., Portman, Neil, Phan, Zoe, Milioli, Heloisa H., Nikolic, Iva, Cadell, Antonia L., Croucher, David R., Simpson, Kaylene J., Lim, Elgene, Hickey, Theresa E., Millar, Ewan K. A., Alves, Carla L., Ditzel, Henrik J., Caldon, C. Elizabeth
Format:	Journal Article
Language:	English
Published:	London BioMed Central 19.08.2025 BioMed Central Ltd Springer Nature B.V BMC
Subjects:	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 Endocrine therapy ER+ breast cancer JNK signalling Palbociclib CDK4/6 inhibition
ISSN:	1756-9966, 0392-9078, 1756-9966
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Summary:	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.
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ISSN:	1756-9966 0392-9078 1756-9966
DOI:	10.1186/s13046-025-03466-9