A study led by researchers at the Garvan Institute of Medical Research has uncovered why some breast cancers become resistant to treatment, potentially opening the door to more effective therapies for patients.
Published today in the Journal of Experimental & Clinical Cancer Research , the study reveals how disruption to a cellular stress response system involving the JNK pathway allows estrogen receptor-positive (ER+) breast cancer cells to evade treatment.
ER+ breast cancer accounts for approximately 70% of all breast cancer diagnoses. While often considered to have a better prognosis than other types of breast cancer, it still accounts for more than 2000 deaths per year in Australia. In most cases, this mortality is caused by resistance to endocrine therapies, leading to metastatic recurrence after what appeared to be successful initial treatment.
Recently, CDK4/6 inhibitors combined with endocrine therapy were approved as first-line therapy for high-risk ER+ breast cancer patients in Australia. While this combination has significantly improved survival rates, some patients still don't respond, and the exact mechanisms behind drug resistance remain unclear. Understanding these mechanisms is therefore crucial for improving outcomes.
Muting the cell's stress response system
The JNK pathway acts like a cellular alarm system – when cells experience stress, such as from cancer treatments, it helps trigger processes that either kill the damaged cells or stop them from dividing. The research team found that when this pathway is inactivated, cancer cells develop resistance to the combination of endocrine treatment and CDK4/6 inhibitors.
Lead author of the study, Associate Professor Liz Caldon, says it's clear the pathway plays a crucial role in how cancer cells respond: "We've identified a mechanism behind treatment resistance in ER+ breast cancer. When key genes in this pathway, including one called MAP2K7, are not functioning properly, breast cancer cells no longer receive the message to stop growing or die, even when damaged with therapy."
From lab discovery to potential impact
To identify which genes influence treatment response, the team performed a genome-wide CRISPR screen, where each gene in the genome is systematically turned off.
"When we knocked out genes involved in the JNK pathway, cancer cells continued to grow despite treatment," says the study's first author, Dr Sarah Alexandrou. "These cells also spread to form more metastases in preclinical models."
To validate the findings, they analysed tumour samples from 78 patients with ER+ breast cancer who had received treatment. Those whose tumours had low activity of the JNK pathway were less likely to respond well.
"As the combination of endocrine therapy and CDK4/6 inhibitors becomes more widely used for breast cancer, doctors urgently need ways to identify who is at most risk of disease progression during their care," Associate Professor Caldon says. "By screening for JNK activity levels in people with high-risk ER+ breast cancers, we have 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."
Challenging previous understanding
While the JNK pathway has often been considered cancer-promoting in some contexts, this study shows it can also act as a tumour suppressor in ER+ breast cancer.
"Too much and too little JNK activity can be problematic – in the context of response to endocrine therapy and CDK4/6 inhibitors, loss of the pathway is clearly detrimental to treatment effectiveness by driving resistance," says Dr Alexandrou.
The team is now investigating what alternative treatments might work for patients with low JNK pathway activity, hoping to develop therapeutic approaches tailored to this group.
"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," says Associate Professor Caldon. "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."
This study was generously supported by the National Breast Cancer Foundation, Estée Lauder Companies Breast Cancer Award, the Lysia O'Keefe Fellowship, Marina Rizzo, Santina Rizzo and Yasmina Sadiki, the Mavis Robertson Fellowship and an Australian government RTP scholarship.
"The National Breast Cancer Foundation is proud to have supported this important research, which is paving the way for more personalised and effective treatment options for people with ER+ breast cancer. Insights like these bring us closer to ensuring every person receives the therapy that's right for them," says Dr Julie Ince-Demetriou, Executive Director, Research at the National Breast Cancer Foundation.
