New Approach Could Identify Treatment Resistant Breast Cancer Patients

While these cancers often have better prognoses, they still account for over 2,000 deaths annually in Australia, largely due to resistance to endocrine therapy that causes recurrence after initial treatment. Although combining CDK4/6 inhibitors with endocrine therapy has improved survival rates, many patients remain resistant, underscoring the need to uncover why treatment failure occurs. Now, a new study has revealed how disruption of a key cellular stress pathway allows ER+ breast cancer cells to evade therapy, creating the potential to identify those who would likely not respond to this combination treatment and direct them instead to other treatments that may have better health outcomes.

The research, led by the Garvan Institute of Medical Research (Sydney, Australia), focused on the JNK pathway, a stress response system that acts as an alarm when cells are damaged by treatments. Normally, this pathway helps cells stop dividing or undergo cell death. However, when inactivated, breast cancer cells ignore stress signals and continue dividing, driving resistance to endocrine therapy and CDK4/6 inhibitors. To identify the mechanisms involved, researchers conducted a genome-wide CRISPR screen to systematically switch off genes.

They discovered that loss of JNK pathway genes, including MAP2K7, allowed cancer cells to grow despite therapy and increased metastatic spread in preclinical models. The findings, published in the Journal of Experimental & Clinical Cancer Research, were further validated through analysis of tumor samples from 78 ER+ breast cancer patients. Those with low JNK pathway activity showed poorer responses to treatment. This highlighted that JNK activity could serve as a predictive marker for determining who is most at risk of therapy resistance, offering an important step toward more tailored treatment approaches.

These insights could transform patient management by allowing doctors to test for JNK activity before starting therapy. Patients with intact pathways may continue to benefit from combination treatment, while those with disrupted pathways could be directed toward alternative options. The team is now investigating potential therapies for patients with low JNK activity, aiming to create personalized treatment strategies for improved outcomes.

“The ultimate goal is to be able to test a patient’s tumour for JNK activity before treatment, allowing doctors to select the most effective therapy for each individual,” Liz Caldon, Associate Professor and lead author of the study. “For those with an intact JNK pathway, combination endocrine therapy and CDK4/6 inhibition is more likely to be effective. For others, we are working on identifying alternative treatments.”

Related Links:
Garvan Institute of Medical Research