A new metabolic pathway explains resistance of certain cancers to treatment

A research team from the Cancer Metabolism and Tumor Microenvironment Laboratory at the University of Liège has uncovered a previously unrecognized mechanism that promotes cancer cell survival under therapeutic pressure. Published in MedComm, the study shows how a key enzyme in lipid metabolism, stearoyl-CoA desaturase-1 (SCD1), cooperates with an epigenetic regulator to support tumor growth.

Led by Professor Nor Eddine Sounni, the team investigated how cancer cells adapt to hostile conditions such as hypoxia, nutrient deprivation, and exposure to anticancer therapies. These cells reprogram their metabolism, particularly lipid metabolism, to sustain proliferation. While SCD1 has long been associated with aggressive tumor behavior, the precise molecular mechanisms underlying its role in therapy resistance remained poorly understood.

The researchers discovered that SCD1 physically interacts with HDAC2, a major regulator of gene expression and protein activity. This interaction promotes the deacetylation of nucleophosmin-1 (NPM1), a multifunctional protein involved in cellular stress responses and in the regulation of the tumor suppressor p53 pathway.

This newly identified molecular axis, SCD1–HDAC2–NPM1, enhances cancer cell survival under oxidative stress and promotes tumor growth. “Our work reveals an unexpected link between lipid metabolism and the post-translational regulation of a tumor suppressor-related pathway,” explains Professor Nor Eddine Sounni. “This discovery provides new insight into how tumor cells adapt to stress and highlights a promising combined therapeutic strategy.”

To validate their findings, the researchers used breast and colorectal cancer cell lines as well as mouse models. They demonstrated that inhibition of SCD1 sensitizes cancer cells to HDAC inhibitors, agents already used in oncology. The combination of these approaches produced a synergistic antitumor effect, improving treatment efficacy.

These results pave the way for new therapeutic strategies targeting both lipid metabolism and epigenetic mechanisms. Such approaches could be particularly relevant for treatment-resistant cancers, where therapeutic options remain limited.

More broadly, the study highlights the growing importance of metabolic vulnerabilities in oncology. By disrupting the molecular systems that cancer cells rely on to survive and adapt, combination therapies could enhance treatment response and reduce relapse risk.

The fact that this molecular pathway was observed across multiple cancer types also suggests potential applications beyond a single tumor context.