Synergy between inhibitors of two mitotic spindle assembly motors undermines an adaptive response

Area of Science:

• Cell Biology
• Molecular Biology
• Cancer Therapeutics

Background:

• Mitosis is crucial for cell division, and its deregulation is common in cancer, making mitosis-specific proteins attractive therapeutic targets.
• Eg5 kinesin inhibitors show promise for cancer therapy, but clinical efficacy is limited, potentially due to the compensatory action of kinesin KIF15.
• KIF15 can drive spindle assembly independently of Eg5, suppressing the cytotoxic effects of Eg5 inhibitors (K5Is).

Purpose of the Study:

• To investigate the hypothesis that combining K5Is with KIF15 inhibitors will yield greater cytotoxicity than either agent alone.
• To identify and characterize small molecule inhibitors of KIF15 motor activity.
• To evaluate the role of KIF15 in mediating resistance to K5Is.

Main Methods:

• High-throughput screening was employed to identify KIF15 inhibitors.
• In vitro and cellular assays were used to assess inhibitor activity, selectivity against other motor proteins, and effects on microtubule binding.
• Studies were conducted to determine if KIF15 inhibition impacts cellular resistance to K5Is.

Main Results:

• Two novel inhibitors targeting KIF15 motor activity were identified.
• These inhibitors demonstrated selectivity for KIF15 over other molecular motors and modulated KIF15's interaction with microtubules.
• Chemical inhibition of KIF15 was found to reduce the development of resistance to K5Is in cells.

Conclusions:

• KIF15 plays a central role in the resistance mechanism against Eg5 inhibitors (K5Is).
• The identified KIF15 inhibitors are valuable tools for studying KIF15 function in physiological contexts.
• Combining KIF15 and Eg5 inhibitors represents a promising strategy for enhancing anticancer therapy efficacy.