KIF15 nanomechanics and kinesin inhibitors, with implications for cancer chemotherapeutics

Abstract

Significance Eg5, a mitotic kinesin, has long been an anticancer drug target. However, a different kinesin motor, KIF15, can rescue cell division when Eg5 is incapacitated, leading to chemotherapeutic resistance. We characterized KIF15 motor mechanics at the single-molecule level and studied the effects of combinations of small-molecule inhibitors of KIF15 and Eg5 on admixtures of motors in a motility assay, as well as on cancer cell proliferation. Taken together, our results point the way toward a strategy of combination drug therapy targeting both Eg5 and KIF15 as a means of overcoming KIF15-mediated cancer resistance. This work highlights the importance of understanding the molecular physiology of different kinesins and of exploring inhibitors that target additional mitotic kinesins.