Credit: PNAS
Researchers have discovered how a molecule called CUL5 helps HSP90 inhibitors kill cancer cells, according to a study published in Proceedings of the National Academy of Sciences.
The team found that CUL5 is required for the degradation of proteins that promote cancer cell proliferation, and CUL5 works in opposition to HSP90.
When cancer cells are treated with HSP90 inhibitors, CUL5 immediately steps in to help dispose of the proliferation-promoting proteins.
Based on these findings, the researchers speculate that some patients may be resistant to HSP90 inhibitors if their cancer cells have lower amounts of CUL5. And conversely, the drugs may work better in patients with higher CUL5 levels.
Paul Workman, PhD, of The Institute of Cancer Research in London, UK, and his colleagues conducted this research in cell lines of melanoma, as well as colon, breast, and lung cancers.
They first tested the HSP90 inhibitor 17-AAG in HT29 cells and found that CUL5 is involved in the drug-induced degradation of several protein kinase clients of HSP90.
Then, the researchers assessed the effects of silencing CUL5 and discovered that it delays the abrogation of protein signaling caused by an HSP90 inhibitor.
Furthermore, silencing CUL5 reduced cellular sensitivity to 3 different HSP90 inhibitors across the 4 different cancer types studied, which, as the researchers pointed out, are driven by different protein kinases.
So the team believes this research could apply to a number of different cancers. HSP90 inhibitors have proven effective against a range of malignancies, including leukemias, lymphomas, and multiple myeloma.
“We’ve known for some time that drugs that block HSP90 have great potential as treatments for cancers . . . , and we had an initial clue that the protein CUL5 may be involved in some way in how these drugs work,” Dr Workman said.
“Our new research shows that CUL5 is not only vital in the response of cancer cells to HSP90 inhibitors but also reveals surprising insights into precisely how it works by acting at several different levels. What also surprised us was that CUL5 gets rid of many more of the cancer-causing proteins than we’d previously imagined and that it’s effective across several types of tumor.”
“This suggests that a test for CUL5 in patients could help us tell whether they might respond to HSP90-blocking drugs, as well as pointing to new targets to develop more effective drugs.”
