Conditional vulnerability

Centrosomes are cellular organelles that help parcel out equal numbers of chromosomes to daughter cells in the late stages of cell division. But many types of cancer cells can complete that process—chromosomal segregation—even when they lack centrosomes, as Ludwig researchers led by Karen Oegema and Andy Shiau reported in Science in 2015. That study found that centrinone, a highly specific inhibitor of PLK4, an enzyme essential for centrosome formation, could reversibly deplete centrosomes from a broad panel of cancer cells but did not block their division. In a study reported in Nature in September, a Ludwig San Diego team led by Karen, Arshad Desai and Franz Meitinger demonstrated that specific cancers might indeed be sensitive to PLK4 inhibition. That sensitivity, they showed, depends on the presence of a second enzyme, the ubiquitin ligase TRIM37. When this enzyme is at low levels, cancer cells continue dividing despite PLK4 inhibition. Cancer cells with high levels of TRIM37, however, stop proliferating under such conditions. Notably, subsets of breast cancers and neuroblastomas with known chromosomal abnormalities overexpress TRIM37. The researchers detailed the mechanism of this vulnerability and showed that TRIM37 over-expression could serve as a marker of cancers likely to respond to treatment with an improved PLK4 inhibitor, like those under development by Andy Shiau and Ludwig’s Small Molecule Discovery program.

This article appeared in the December 2020 issue of Ludwig Link. Click here to download a PDF (1 MB).


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