Medication-based starvation of cancer cells

Previous studies have shown that IMiDs bind to a protein called cereblon, which results in the malfunction of a protein complex on the surface of tumor cells, thus inhibiting tumor growth. A research team led by Prof. Florian Bassermann and Vanesa Fernández of the university hospital Klinikum rechts der Isar of TUM has now deciphered the exact mechanism and the scope of this dysregulation in a new study.

They discovered that cereblon supports the protein HSP90 as what is known as a co-chaperone; HSP90 is responsible for the correct folding of thousands of proteins in human cells. The scientists were able to show that the support function of the co-chaperone cereblon is specific for membrane proteins. These proteins, which are anchored on the surface of a cell, are essential for tumor cells to grow: They enable cells to communicate with neighboring cells, they pass on growth signals and take in important nutrients.

Upon IMiD-treatment, cereblon can no longer bind to the HSP90 machinery, and as a result loses its supportive function in the quality control of membrane proteins. “Using proteome-wide analyses, we were able to show that a large number of essential proteins on the surface of cancer cells are destabilized by IMiD-treatment,” says oncologist Florian Bassermann. “This ultimately explains the unusually broad effects of these substances.”

In multiple myeloma the proteins CD98hc and LAT1 are particularly affected. Together these proteins usually ensure that cancer cells are supplied with amino acids. Since cancer cells in the case of multiple myeloma have an especially high need for nutrients like amino acids, CD98hc and LAT1 are very abundant proteins in these cells. The research team has now shown that IMiD-treatment significantly reduces the uptake of essential amino acids and thus inhibits the growth of the tumor cells. “This literally starves out the cancer cells,” explains Michael Heider, first author of the study.