Maximizing Anticancer Response with MPS1 and CENPE Inhibition Alongside Apoptosis Induction

Antimitotic compounds targeting key spindle assembly checkpoint (SAC) regulators, such as MPS1, Aurora kinase B, PLK1, KLP1, and CENPE, offer potential alternatives to traditional microtubule-targeting agents like paclitaxel. These compounds aim to address the resistance and adverse effects often associated with microtubule-targeting drugs. Antimitotics are classified as either mitotic blockers, which induce SAC-mediated mitotic arrest, or mitotic drivers, which force cells to bypass the SAC, resulting in aberrant mitosis. Despite their progression to clinical trials, these agents have shown limited efficacy as monotherapies, likely due to heterogeneous cell fate responses influenced by cyclin B degradation dynamics and apoptotic signaling pathways.

To address this limitation, we evaluated the impact of combining BH3-mimetics, which inhibit anti-apoptotic signals, with antimitotics in lung cancer cells. Specifically, we studied the effects of the BH3-mimetic navitoclax in conjunction with the selective CENPE inhibitor GSK923295 (a mitotic blocker) and the MPS1 inhibitor BAY1217389 (a mitotic driver). Our goal was to direct cancer cells towards apoptosis. BH3-mimetic combinations with both mitotic blockers and drivers significantly enhanced cancer cell death via apoptosis in both 2D and 3D culture systems, while demonstrating lower toxicity in non-tumor cells. These findings underscore the therapeutic potential of combining BH3-mimetics with clinically advanced antimitotic agents to improve treatment efficacy.