A University of Alberta research team has uncovered a new role for a genetic mutation previously known to be linked to developmental disorders — and it could hold the key to more effective treatments and improved outcomes for cancer patients.
In new research published in Science Advances, the team outlines a previously unknown function for a protein calledmacrophage erythroblast attacher, or MAEA. It controls cell repair and replication, and when it's removed or inhibited, the cells become more vulnerable to chemotherapy drugs, the researchers report.
"Because of the new function of MAEA in DNA repair, our preliminary experiments suggest that we can reverse drug resistance," says principal investigator Ismail Ismail, associate professor in the Department of Oncology. "We think that our new understanding of this function could improve treatment options for both developmental disorders and cancer."
The team tested MAEA's impact using chemotherapy treatments that are typically used for colorectal, small-cell lung and ovarian cancers. They screened almost 900 genes to identify which ones were involved in the cell's defence against the drugs.
Once they zeroed in on MAEA's role in cell repair and replication, they partnered with biochemistry professor Mark Glover to use AlphaFold modelling, an AI-based prediction tool, to model the impact of gene mutations found in kids with developmental disabilities on the newly identified function of MAEA.
They also worked with a research team at Université Laval to identify the compensatory pathway cancer cells use when MAEA is not working properly, with the idea that combined treatment could block both pathways at once.
The U of A team is now working with an American cancer group to test the approach on tissue collected from cancer patients who have relapsed and have no other treatment options. They are also testing it with other classes of chemotherapy drugs.
A research group at the University of Cambridge has independently reproduced the U of A team's findings.
MAEA was previously thought to be exclusively involved in red blood cell development, and its dysfunction has been linked to neurodevelopmental delays and facial abnormalities.
First author Elham Zeinali, a PhD student, says the new research offers a better understanding of how mutations in the gene can affect children during development.
"We also know some specific cancers produce more of the protein created by the MAEA gene, so we hope to target MAEA with drugs to improve outcomes for patients taking chemotherapy," Zeinali says.
While designing new drugs to target MAEA could take several years, Ismail sees potential to use the gene soon as a biomarker to identify which patients will respond best to chemotherapy.
The research was funded by Cancer Research Institute of Northern Alberta (CRINA) bridge funding provided by Terry and Betty Davis and by the Canadian Institutes of Health Research. Elham Zeinali received a scholarship from the Yau Family Foundation and the Alberta Cancer Foundation/Antoine Noujaim Entrance Award. Ismail Ismail is a member of CRINA and the Women and Children's Health Research Institute. Some of the research was carried out in the Cross Cancer Institute Cell Imaging Facility.
