Centrosome amplification (CA) is a hallmark of virtually all types of cancers including solid tumors and hematological malignancies. Cancer cells with extra centrosomes use centrosome clustering (CC) to allow for successful division. Because normal cells do not rely on this mechanism, CC is regarded as a promising target to selectively eradicate cells harboring supernumerary centrosomes. To identify novel inhibitors of CC, we developed a cell-based high-throughput screen that reports differential drug cytotoxicity for isogenic cell populations with different centrosome contents. We identified CP-673451 and crenolanib, two chemically related compounds originally developed for inhibition of PDGFR-beta, as robust inhibitors of CC with selective cytotoxicity for cells with extra centrosomes. We demonstrate that these compounds induce mitotic spindle multipolarity by activation of the actin severing protein cofilin, leading to destabilization of the cortical actin network, and provide evidence that this activation is dependent on slingshot phosphatases 1 and 2 but unrelated to PDGFR-beta inhibition. More specifically, we found that although both compounds attenuated PDGF-BB-induced signaling, they significantly enhanced the phosphorylation of PDGFR-beta downstream effectors, Akt and MEK, in almost all tested cancer cell lines under physiological conditions. In summary, our data reveal a novel mechanism of CC inhibition depending on cofilin-mediated cortical actin destabilization and identify two clinically relevant compounds interfering with this tumor cell specific target.
Type of Publication:
Journal article published