Northwestern University team led by Drs. Abdulkadir and Schiltz publish new research that defines that therapeutic effect of their small molecule MYC inhibitors on cancer cell metabolism.

A research team at Northwestern University, led by Vortex Therapeutics founders Dr. Sarki Abdulkadir and Dr. Gary Schiltz, has published new findings that define the therapeutic effect of their small-molecule MYC inhibitors on cancer cell metabolism. The groundbreaking work, published in the journal Science Advances (PMID: 40668928), identifies a critical metabolic weakness that can be exploited to enhance the efficacy of MYC-targeted therapies.

The study centers on the MYC oncogene, a known driver of tumor growth in up to 70% of human cancers, which is notoriously challenging to drug. The researchers utilized a genome-wide CRISPR screen in combination with their small-molecule inhibitor, MYCi975, to map the synergistic pathways.

The key discovery is a synthetic lethality when MYC inhibition is paired with the disruption of mitochondrial complex I components.

The research details the mechanism:

• Dual Metabolic Effect: MYC inhibition via MYCi975 initially reduces both oxidative phosphorylation (OXPHOS) and glycolysis in cancer cells.
• Compensatory Rewiring: This metabolic stress triggers a compensatory survival mechanism, specifically the upregulation of genes related to mitochondrial complex I.
• Exploitable Vulnerability: By subsequently targeting complex I through genetic or pharmacological means, the researchers created a “double-hit” that sensitized tumors to MYCi975 treatment.

“For the first time, we have systematically identified a metabolic adaptation mechanism that MYC-driven tumors use to survive drug treatment,” said Dr. Sarki Abdulkadir, Principal Investigator. “This research provides a clear, rational strategy for combining our emerging MYC inhibitors with existing or well-characterized metabolic drugs, like metformin, to significantly improve treatment outcomes.”

The study also found that this combination therapy led to increased infiltration of immune cells, specifically and macrophages, into the tumors, suggesting a triple benefit of directly hitting MYC, disrupting metabolic compensation, and boosting the anti-tumor immune response.

This work lays a strong foundation for the clinical development of MYCi975 by establishing a precise combination strategy to maximize its therapeutic potential against aggressive, therapy-resistant cancers.