Collectively, this study suggest that inhibition of proteasome causes mitotic arrest and subsequent multi-polar spindle formation of tumor cells, resulting in mitotic catastrophe via caspase-3/GSDME-dependent pyroptosis; proteasome inhibitor also activates WEE family kinases (WEE1 and PKMYT1) to induce G2-phase arrest, and inhibition of WEE family kinases potentiates proteasome inhibitor-induced pyroptosis by promoting mitotic entry. Here, PKMYT1 is linked to neoplasm.