Jerusalem, 20 October, 2025 (TPS-IL) — A new international study led by Israeli and German scientists **have** uncovered a protein system that could help explain why some colorectal cancer patients fail to respond to chemotherapy.
The findings, published in the peer-reviewed journal, Molecular Oncology, open the door to more personalized and effective treatments for one of the world’s deadliest cancers.
Colorectal cancer is the third leading cause of cancer-related deaths globally. Depending on the stage of the disease, it is typically treated by a combination of approaches, such as chemotherapy, radiation therapy, immunotherapy, surgery, targeted therapy, and palliative care.
While chemotherapy remains a mainstay of treatment, many patients experience drug resistance that limits its effectiveness. Seeking to understand why, scientists from Hebrew University of Jerusalem, University Medicine Magdeburg, and Otto-von Guericke University analyzed tumor and healthy tissue samples from 32 colorectal cancer patients, integrating advanced sequencing, histological analysis, and patient-derived tumor models.
The team — led by Prof. Michal Linial, Prof. Or Kakhlon, and researcher Keren Zohar of the Hebrew University, together with Prof. Ulf D. Kahlert and Dr. Marco Strecker of University Medicine Magdeburg — identified a crucial role for a protein system known as the cystine/glutamate transporter, or Xc-. This system helps cancer cells manage oxidative stress and resist programmed cell death, allowing tumors to survive chemotherapy.
“Our study shows the power of integrating patient-specific data with functional models,” said Linial. “This approach doesn’t just identify what makes each patient’s tumor unique, it shows us where the cancer is most vulnerable.”
The researchers focused on the gene SLC7A11 (also known as xCT), which was consistently overexpressed in tumor samples. Working together with a partner gene, it forms the Xc- transporter—a molecular mechanism that enables cancer cells to absorb cystine and expel glutamate, maintaining the balance needed for survival under treatment stress.
When scientists disrupted this transporter system in laboratory experiments and patient-derived organoids, the tumors became more sensitive to chemotherapy. They also discovered a distinctive protein “signature” on tumor cell surfaces that could serve as a biomarker to predict which patients are likely to resist standard treatments.
“These findings could help design new therapies that are both more effective and more personalized, offering hope for patients facing this devastating disease,” said Kahlert.
The study also highlights the importance of ferroptosis, a form of programmed cell death that cancer cells often evade. Because the same molecular pathways are involved in neuronal protection, the researchers believe their findings could have implications beyond colorectal cancer, potentially informing studies of other cancers and neurological disorders.
According to the team, bioinformatic analyses conducted by Keren Zohar were critical to isolating patient-specific factors that drive drug resistance. By comparing each tumor sample to a healthy sample from the same patient, the researchers were able to overcome the natural variability between tumors and pinpoint precise molecular differences linked to treatment outcomes.
The discovery positions the Xc- transporter as a predictive therapeutic target and reinforces the potential of personalized pharmacogenomics — the study of how genes affect a person’s response to drugs—to guide future cancer care.
“The more we understand the molecular ‘fingerprints’ that define each tumor, the closer we get to treatments that truly fit the patient, not just the disease,” Linial said.
The discovery could help doctors predict chemotherapy resistance, guide personalized treatment, and inspire new drugs that block the Xc- transporter. Since the same pathways affect neuronal survival, the findings may also aid research into neurological diseases like Alzheimer’s and Parkinson’s.
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