Suppression of JNK Pathway Drives Resistance to Endocrine and CDK4/6 Therapy in ER-Positive Breast Cancer

Treatment of estrogen receptor-positive (ER+) breast cancer is generally successful with the use of endocrine therapy and CDK4/6 inhibitors that typically results in extending patient survival. However, the problem of resistance that is developed over time still remains. In a major study in the Journal of Experimental & Clinical Cancer Research, the researchers have now identified the suppression of the c-Jun N-terminal kinase (JNK) signaling pathway, particularly through loss of MAP2K7, as a central mechanism of this resistance.¹

Image Credit: Valerii Apetroaiei | stock.adobe.com

Using genome-wide CRISPR/Cas9 knockout screens in ER+ breast cancer cell lines (MCF-7 and T-47D), investigators pinpointed MAP2K7, the kinase upstream of JNK, as vital for sensitivity to combined endocrine therapy and CDK4/6 inhibition. Knockout of MAP2K7 disrupted downstream JNK activation, impairing activation of the AP-1 transcription factor (via c-JUN). In this way, cancer cells not only stopped the stress reactions such as aging and apoptosis, but they were also able to keep proliferating under therapy pressure. Besides that, in experimental models the absence of MAP2K7 was connected with the increased ability of metastatic potential.¹

Analysis of tumor datasets uncovered that tumors characterized by low JNK signaling activity, indicated by both lowered MAP2K7 expression and diminished phosphorylated JNK level, correlated with poorer prognosis and a milder reaction to the standard therapy. Patients whose tumors belonged to this category were statistically under a higher risk of relapse during or after treatment.¹

The results were also pointed out in a news release that emphasized the translational potential of the findings and suggested that in the future, assessing the condition of the JNK pathway may assist clinicians in locating patients who are unlikely to react to the existing treatment regimen.²

Future insight was derived from Inside Precision Medicine, which depicted the JNK pathway as a vital "cellular alarm" system. Sarah Alexandrou, PhD, first author of the study, stated, “When we knocked out genes involved in the JNK pathway, cancer cells continued to grow despite treatment—they also spread to form more metastases in preclinical models.” The piece underlined that disabling the JNK signal compromises therapy effectiveness and supports the concept of pre-treatment biomarker screening to guide personalized therapeutic decisions.³

These discoveries offer several implications for oncology pharmacists and the broader care team. By using biomarker-driven patient stratification, clinicians could evaluate JNK pathway activity, for instance, by looking at MAP2K7 expression or the levels of pJNK to determine which patients are most likely to benefit from endocrine and CDK4/6 therapies and which may require alternative treatment strategies. Pharmacists will also play an important role in patient education and counseling, helping individuals understand the rationale for personalized approaches and the value of biomarker testing in guiding therapy decisions. Finally, the research issues a warning for drug development, as JNK is indicated as a tumor suppressor in this scenario. Drugs that mistakenly destroy the pathway may lessen the power of therapy and cohere resistance, thereby reminding us of the necessity of precise therapeutic design.

Suppression of the JNK signaling pathway, particularly through loss of MAP2K7, is emerging as a robust driver of resistance to endocrine therapy combined with CDK4/6 inhibition in ER+ breast cancer. By disabling stress response mechanisms, cancer cells evade treatment and gain metastatic capabilities. Incorporating JNK pathway assessment into clinical workflows offers a promising opportunity to personalize therapy and improve outcomes. As precision oncology evolves, testing for biomarkers like JNK activity may become critical in the management of ER+ disease.^1-3

REFERENCES

1. Alexandrou S, Lee CS, Fernandez KJ, et al. JNK pathway suppression mediates insensitivity to combination endocrine therapy and CDK4/6 inhibition in ER+ breast cancer. Journal of Experimental & Clinical Cancer Research. 2025;44(1). doi:10.1186/s13046-025-03466-9

2. Researchers uncover potential mechanism driving treatment resistance in common breast cancer. EurekAlert! Published August 18, 2025. https://www.eurekalert.org/news-releases/1094843

3. Warneck-Silvestrin L. ER+ Breast Cancer: New Discovery Explains Treatment Resistance. Inside Precision Medicine. Published August 20, 2025 https://www.insideprecisionmedicine.com/topics/oncology/er-breast-cancer-new-discovery-explains-treatment-resistance/