Researchers may have uncovered a major factor contributing to treatment resistance in patients with colorectal cancer, according to a recent study published by Mzoughi et al in Nature Genetics.
Background
Colorectal cancer is one of the deadliest cancer types across the world, with treatment resistance posing a significant barrier to long-term survival. Prior research has focused on targeting a harmful population of tumor cells known as LGR5-positive cancer stem cells; however, researchers have been unable to achieve durable tumor regression.
Study Methods and Results
In the recent study, investigators discovered that some LGR5-positive colorectal cancer cells may revert to a fetal-like state, helping them survive and grow despite treatment. The phenomenon, known as oncofetal reprogramming, could enable the cancer cells to diversify their molecular characteristics and behavior, thereby rendering them resistant to current chemotherapies.
The researchers also discovered strategies to block the process of oncofetal reprogramming, which could make current cancer treatments more effective.
“Our data suggest that inhibiting the oncofetal program in combination with current treatments may provide a powerful approach to overcoming therapy resistance,” hypothesized senior study author Ernesto Guccione, PhD, Professor of Oncological Sciences at Mount Sinai.
Conclusions
“This discovery challenges the conventional belief that colorectal cancer is driven by a single, uniform cancer stem cell population,” indicated lead study author Slim Mzoughi, PhD, Assistant Professor of Oncological Sciences at the Icahn School of Medicine at Mount Sinai. “Instead, we demonstrate that multiple distinct cancer stem cell states coexist and cooperate, significantly influencing tumor progression and therapy resistance.”
For clinicians, these findings may offer a deeper understanding of why certain patients with colorectal cancer experience treatment resistance and disease recurrence. Future therapeutic strategies integrating inhibitors of the oncofetal program with existing chemotherapy regimens could improve patient outcomes and extend survival.
“This study lays the groundwork for the development of novel targeted therapies that could benefit patients [with colorectal cancer] worldwide,” underscored Dr. Guccione.
The researchers are currently working to develop new therapies or repurpose drugs already approved by the U.S. Food and Drug Administration to effectively target oncofetal reprogramming.
Disclosure: The research in this study was funded by the National Cancer Institute of the National Institutes of Health. For full disclosures of the study authors, visit nature.com.
