A team of scientists at the Garvan Institute of Medical Research has discovered that inactivation of a stress pathway makes ER+ breast cancer cells ignore stress signals, allowing them to evade treatment.
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 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 2,000 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 analyzed tumor samples from 78 patients with ER+ breast cancer who had received treatment. Those whose tumors 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 tumor 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 tumor 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.”
More information:
JNK pathway suppression mediates insensitivity to combination endocrine therapy and CDK4/6 inhibition in ER+ breast cancer, Journal of Experimental & Clinical Cancer Research (2025). DOI: 10.1186/s13046-025-03466-9
Citation:
Researchers uncover potential mechanism driving treatment resistance in common breast cancer (2025, August 18)
retrieved 18 August 2025
from https://medicalxpress.com/news/2025-08-uncover-potential-mechanism-treatment-resistance.html
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no
part may be reproduced without the written permission. The content is provided for information purposes only.
A team of scientists at the Garvan Institute of Medical Research has discovered that inactivation of a stress pathway makes ER+ breast cancer cells ignore stress signals, allowing them to evade treatment.
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 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 2,000 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 analyzed tumor samples from 78 patients with ER+ breast cancer who had received treatment. Those whose tumors 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 tumor 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 tumor 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.”
More information:
JNK pathway suppression mediates insensitivity to combination endocrine therapy and CDK4/6 inhibition in ER+ breast cancer, Journal of Experimental & Clinical Cancer Research (2025). DOI: 10.1186/s13046-025-03466-9
Citation:
Researchers uncover potential mechanism driving treatment resistance in common breast cancer (2025, August 18)
retrieved 18 August 2025
from https://medicalxpress.com/news/2025-08-uncover-potential-mechanism-treatment-resistance.html
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no
part may be reproduced without the written permission. The content is provided for information purposes only.
